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EP0177016A2 - Pyridyloxy derivatives - Google Patents

Pyridyloxy derivatives Download PDF

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Publication number
EP0177016A2
EP0177016A2 EP85112416A EP85112416A EP0177016A2 EP 0177016 A2 EP0177016 A2 EP 0177016A2 EP 85112416 A EP85112416 A EP 85112416A EP 85112416 A EP85112416 A EP 85112416A EP 0177016 A2 EP0177016 A2 EP 0177016A2
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EP
European Patent Office
Prior art keywords
oxy
pyridyl
butenylamino
cis
piperidinomethyl
Prior art date
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EP85112416A
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German (de)
French (fr)
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EP0177016A3 (en
EP0177016B1 (en
Inventor
Fujio Nohara
Tomoaki Fujinawa
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Ikeda Mohando Co Ltd
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Ikeda Mohando Co Ltd
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Priority claimed from JP20669084A external-priority patent/JPS6185365A/en
Priority claimed from JP5020785A external-priority patent/JPS61207375A/en
Application filed by Ikeda Mohando Co Ltd filed Critical Ikeda Mohando Co Ltd
Publication of EP0177016A2 publication Critical patent/EP0177016A2/en
Publication of EP0177016A3 publication Critical patent/EP0177016A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to pyridyloxy derivatives, and more particularly to aminoalkylpyridyloxy derivatives and medically acceptable salts, hydrates and solvates thereof which exert antagonism to histamine H 2 - receptors and thus have utility in medical treatment of digestive ulcers.
  • gastric acid secretion can be controlled by blocking the histamine H 2 -receptors from the histamine action and that gastric secretion in an animal or a human being can be suppressed by the use of a substance having an antagonism to the histamine H 2 -receptors.
  • Cimetidine which has been marketed as the first commercially available medicine for treating digestive ulcers.
  • the object of this invention is to provide novel substituted aminoalkylpyridyloxy derivatives which exert superior antagonism to histamine H 2 -receptors to suppress gastric secretion of animals appreciably and which also provide shielding functions to protect the mucous membrane and to promote the secretion of mucus.
  • the compounds provided by the present invention are aminoalkylpyridyloxy derivatives represented by the general formula: wherein X is (wherein Rl and R 2 are individually hydrogen atoms or lower alkyl groups having 1 to 6 carbon atoms, or Rl and R2 form, together with the bonded nitrogen atom, a four to eight-membered heterocyclic ring which may have a further substituting group or groups; A is a straight-chain or branched-chain alkylene group having 1 to 6 carbon atoms); and Z is either one of the following groups: or wherein R3, R4, R5, R6, R7, R8, R9, R 10 , Rll , R 12 , R 13 1 R 14 , R 15 , R 16, R 17 and R 18 are individually hydrogen atoms or alkyl groups having 1 to 6 carbon atoms, alkenyl, alkynyl, aralkyl, heterocyclic aryl alkyl groups; or a four to eight-membered heterocyclic group is formed respectively by
  • G is a nitrogen or carbon atom, p indicates 0, 1 or 2 and, Q indicates oxygen or sulfur; and medically acceptable salts, hydrates and solvates thereof, and pharmaceutics for digestive ulcers which comprise any of the foregoing as an effective ingredient.
  • examples of the lower alkyl group having 1 to 6 carbon atoms which are included as either one or both of the groups Rl and R2 are methyl, ethyl, n-prpropyl, iso-propyl. n-butyl, s-butyl, t-butyl, n-amyl, and n-hexyl groups.
  • Examples of the hetrocyclic groups formed by the combination of the groups Rl and R 2 together with the nitrogen atom bonded therewith are azetidino-, pyrrolidino-, piperidino- and perhydroazepino- groups.
  • These heterocyclic rings may include further substituent groups, such as hydroxyl, methoxy, ethoxy and lower alkyl groups having 1 to 6 carbon atoms.
  • a substituent X in the general formula defined in the claim should combine with pyridyne ring at the 4th or 6th position thereof.
  • alkylene groups identified by A, include methylene, ethylene, propylene, iso-propylene and isobutylene.
  • the groups R3, to R 2 2 include, for example, alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, n-amyl, iso-amyl and n-hexyl; alkenyl groups, such as ethenyl, 2-propenyl, 2-butenyl and 3-butenyl; alkynyl groups, such as 2-propargyl; aralkyl groups, such as 2-dimethylaminomethylbenzyl, 3-dimethylaminomethylbenzyl, 4-dimethylaminomethylbenzyl and 3-methoxybenzyl; heterocyclic aryl alkyl groups, such as 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-furanylmethyl, 2-thiofur
  • Preferred heterocyclic groups which are formed, respectively, by R3 and R4, R 5 and R 6 , R 7 and R 8, R 10 and R ll, R 13 and R 14 and, R16 and R17, together with the corresponding nitrogen atoms bonded therewith, are azetidino-, pyrrolidino-, piperidino- and 4-methylpiperazino-rings.
  • the compounds of the invention represented by the general formula (1) can be either in the cis or trans geometrical isomer forms.
  • the compounds of the invention represented by the general furmula (1) and the salts thereof can be prepared, depending on the substituents Z included therein, through the following different processes.
  • X, R3 and R 4 are the groups as described hereinbefore and defined in the claims; R20 is a lower alkyl, preferably methyl or ethyl; and E is -0- or -S-, preferably -O-.
  • the first and second steps can be carried out separately, but it- is preferable that they be carried out sequentially without interruption. It is preferred that both of the starting materials be used in the equivalent molar ratio in the first step, whereas in the second step it is preferred that amine be used in an excess amount, for example, in an amount of two to five times the moles of the resultant product of the first step.
  • Both steps can be carried out without using a solvent or may be carried out in an inert organic solvent such as methanol, ethanol, propanol, acetonitrile or chloroform.
  • the reaction temperature ranges generally from -10°C to the boiling point of the solvent used, the boiling points of the usable solvents ranging generally from 50°C to 150°C, and the preferable temperature range is from room temperature to 80oC.
  • the time required for the completion of reaction varies depending on the reaction temperature, and both reactions can be completed within 30 minutes to 24 hours.
  • the pyridyloxybutenylamine derivative used in the first step is a novel compound and can be prepared, for example, by the following process: wherein X is a group as described hereinbefore and defined in the claims, Hal is a halogen atom such as chlorine, bromine, iodine and fluorine, preferably chlorine or bromine.
  • one of the compounds represented by the formula: i.e. the compound can be prepared by the process disclosed by Sidney Cohenet et al, in J. Am. Chem. Soc., 88 (7), 1533 (1966).
  • X, R5 and R 6 are the groups as described hereinbefore and defined in the claims; R30 is a lower alkyl, preferably methyl or ethyl; and F indicates sulfur (-S-) or oxygen (-0-).
  • the compounds used in the first step and represented by the foumula are known compounds, and 3,4-dimethoxy ⁇ 1,2,5-thiaziazole
  • the first step set forth hereinabove can be carried out, for example, by reacting one mole of a derivative of 4- ⁇ (3-dialkylaminoalkyl)pyridyl-2-oxy>-2-butenylamine with one to three moles of 3,4-dimenthoxy-l,2,5-thiadiazole, 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide, or 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide in the absence of a solvent or in an inert organic solvent (preferably a lower alcohol such as methanol, ehtanol or propanol, or acetonitrile or chloroform) at a reaction temperature of from -5°C to 100 o C, preferably from 0°C to 30°C under agitation. The reaction is completed within 30 minutes to 24 hours, and the end of the reaction may be checked by means of T.L.C.(thin layer chromatography).
  • the reaction of the first step may be continued into the reaction of the second step in a continuous operational sequence.
  • the second step operation may be carried out after refining the resultant product of the first step, for example, by means of column chromatography.
  • the second step operation is carried out by dissolving the resultant product of the first step in an inert organic solvent followed by addition of an amine compound represented by the formula: 2 to 10 moles of amine, relative to one mole of the resultant product of the first step, are used; and the second step is carried out generally at a reaction temperature of from -lOoC to 100 o C, preferably from 0°C to 30°C. The reaction is completed within 30 minutes to 24 hours.
  • a compound represented by the formula: can be prepared by the following process.
  • the resultant product of the second step for instance, 3-amino-4- ⁇ 4-(4-dialkylaminoalkylpyridyl-2-oxy)-2-butenylamino>-1,2,5-thiaziazole-1-oxide; can be treated with a mineral acid (for example hydrochloric acid) to obtain tetrahydrochloride of N- 4-(4-dialkyl- aminoalkylpyridyl-2-oxy)-2-butenyl ethanediimidamide.
  • a mineral acid for example hydrochloric acid
  • the product can be reacted with 1 to 10 moles of sulfur monochloride or N,N'-thiobisphthalimide, relative to one mole of the resultant product to convert it into 3- ⁇ 4-(4-dialkylaminoalkypyridyl-2-oxy)-2-butenylamino>-4-amino-1,2,5-thiadiazole.
  • Such a compound can be prepared through the following reaction:
  • such a compound can be prepared by the process including the following first and second steps: wherein X, R 7 , R8 and Hal are the same as defined above.
  • 2,5-dihalogeno-l,3,4-thiaziazole used in the first step can be prepared by a process described in R. Stolle et al, J. Prakt. Chem., 122, 289(1929).
  • the first step can be carried out by reacting one mole of an amine derivative with one to three moles of 2,5-dihalogeno-l,3,4-thiaziazole in the absence of a solvent or in an inert organic solvent (preferably methanol, ethanol, propanol, DMF, DMSO) at a temperature of from 50 to 200°C.
  • an inert organic solvent preferably methanol, ethanol, propanol, DMF, DMSO
  • the reaction can be carried out by heating in a bombenroll or an autoclave at a temperature of higher than the boiling point. It is suitable to use an alcohol. as the solvent, and the reaction temperature ranges from 50°C to 200°C, preferably from 70°C to 100°C.
  • the first step is carried out by reacting starting materials in equivalent moles in the presence of an inert solvent, optionally under heating.
  • the reaction is completed within 20 minutes to 24 hours, and it is preferred that the reaction be carried out at room temperature within 2 to 6 hours.
  • the second step is carried out by reacting the resultant product of the first step with a hydrazine derivative in an organic solvent such as methanol, ehtanol or propanol, and the molar ratio of the hydrazine derivative to the product of the first step is in the range from 1:1 to 10:1 preferably from 1.5:1 to 3:1.
  • the reaction is completed within 30 minutes to 24 hours at a reaction temperature of from room temperature to 150°C, and is preferably carried out at the boiling point of a lower alcohol such as methanol and ethanol within 5 to 10 hours.
  • R 10 and R ll of the product prepared above are hydrogen atoms.
  • Derivatives wherein R1 0 and Rll are other than hydrog.en atoms can be prepared by reacting the product with a compound having an active elimination group such as haloalkyl.
  • N-cyanodialkyldithio-imido-carbonate used in the reaction of the first step is a known compound and can be prepared by a method described in Japanese Patent Publication No. 46-26482.
  • Such a compound can be prepared through the following reaction. wherein X, G and R12 are the same as refined above; and B is R 60 S -( R 60 is a lower alkyl, preferably methyl) or nitroamine (-NH-N0 2 ).
  • the above reaction can be carried out by melting without a solvent at about 150°C or by refluxing in pyridine.
  • the above reaction can be carried out by refluxing in an inert solvent such as ethanol and pyridine.
  • Such a compound can be prepared through the following reaction.
  • X, R13 and R 14 are the same as defined above; and D is a halogen atom (chlorine, bromine or iodine) or a methylthio group.
  • hydrochloride of 6-amino-4-chloro -2 (lH)-pyrimidone can be prepared by the process reported by Wolfgang Pfleiderane et al, in Ann., 657, 149 (1962).
  • the reaction can proceed in a solvent or without using any solvent.
  • Usable solvents include, for example, methanol, ethanol, water, DMF and DMSO.
  • the reaction can proceed at 50°C to 150°C for 5 minutes to 24 hours under agitation.
  • Such a compound can be prepared through the following reaction.
  • the reaction set forth above can proceed at 50°C to 150°C in an inert organic solvent or without using any solvent.
  • inert solvents include alcohols, preferably methanol, ethanol and propanol, and the reaction may proceed preferably under reflux of such a solvent.
  • the compounds represented by the formula: can be prepared by the process reported by C. C. Tzeng et al, in J. Org. Chem., 26, 1118 (1961), or by a modified process thereof, which should be obvious to those having ordinary skill in the art.
  • Cimetidine which has been widely used for clinical applications as a medicine for digestive ulcers as having an antagonistic function on the histamine H 2 -receptor.
  • a male Wistar rat having a body weight of about 160 g and which had not fed for 24 hours was anesthetized by an intraperitoneal dose of 1.2 g/kg of urethane.
  • the gaster anterior was incised and fitting with a double polyethylene cannula.
  • the wall of the stomach was rinsed with 5 ml pf saline at 30 minutes intervals, and the quantity of gastric acid contained in each rinsing solution was measured by titration.
  • the basal acid secretion was initially measured three times, and then 0.2 mg/kg of each of the compounds of this invention was administered subcutaneously and 3 mg/kg of histamine was administered subcutaneously after the lapse of an additional 30 minutes.
  • the quantity of gastric acid secreted after the operation was measured continuously for 3 hours. Within that measurement interval, three time points at which the increase in acid secretion reached a maximum level were selected, and the average quantity of gastric acid secreted at those time points was taken as the increase in acid secretion, which was compared with the increase in acid secretion of the control group to calculate the percent inhibition for secretion of gastric acid (Table 1).
  • a male Hartley guinea pig having a body weight of about 400 g was killed by cervical dislocation, and the atrium thereof was isolated and was suspended in an organ bath containing 50 m of a modified Ringer solution and subjected to a tension of 1 g. The number of heart beats under such condition was recorded using a polygraph.
  • mice Male ddv mice each having a body weight of about 22 g and which had not eaten for 8 hours were orally dosed with the test samples, and the general symptoms and fatalities were observed from the time immediately following the administration to 14 days after the administration.
  • the median lethal dose ,(LD 50 ) was calculated in accordance with the Litchfield and Wilcoxon Method.
  • the inhibitive actions of the respective compounds, prepared by Examples of the invention and administered subcutaneously on gastric acid secretion induced by histamine were greater than that of Cimetidine.
  • the antagonistic actions against Histamine H 2 - receptor of the compounds of this invention were comparable with or superior to that of Cimetidine, when tested using isolated right atria of guinea pigs.
  • the antagonistic actions of the compound of example 15 were strong.
  • Another characteristic effect of the compound of this invention that was ascertained is that the inhibitory effect on gastric acid secretion by the intraduodenal administration, which is similar to oral administration, was extremely high.
  • the compounds prepared, respectively, by Examples 1, 2, 4, 17, 25, 30, 31, 32 and 36 were about 46.6, 25.9, 63.6, 50.0, 50.0, 26.9, 25.0, 32.8 and 41.0 times more effective than the ED 50 value of Cimetidine.
  • the compounds of this invention have remarkable utility when used as anti-pectic ulcer drugs, since they exhibit powerful inhibitory effects against Histamine H 2 -receptor and potent suppression effects on gastric acid secretion and yet are less toxic.
  • the compounds of this invention may be used either in the free form or in the form of acid addition salts thereof.
  • Pharmaceutically acceptable acid addition salts of the compounds of this invention are, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate and organic acid addition salts such as acetate, propionate, citrate, malate, fumarate, methanesulfonate and so forth.
  • Example 2 Preparation of 1-methylamino-2-[4- ⁇ 4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylaminol-1-cyclobuten-3,4-dione: Yield: 54.3% Melting Point: 207 to 210°C (d)
  • IR(KBr, cm-1) 3200, 2950, 1805, 1640, 1570, 1400, 1290, 1160, 1040, 835, 740, 600
  • Example 3 Preparation of 1-amino-2- ⁇ 4-(6-dimethylaminomethyl- pyridyl-2-oxy)-cis-2-butenylamino>-l-cyclobuten-3,4-dione:
  • 2-bromo-4-dimethylaminomethylpyridine in place of 44 grams of 2-bromo-4-(1-piperidinomethyl)pyridine, there was obtained 27.1 g (Yield: 74.2%) of the captioned compound as a light brown oily product.
  • Example 5 Preparation of 1- ⁇ 4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-2-n-hexylamino-1-cyclobuten-3,4-dione: Yield: 24.2% Melting Point: 120 to 122°C (Recrystallized from methanol- hexane) IR(KBr, cm -1 ): 3200, 2950, 1810, 1650, 1580, 1430, 1310, 1150, 1030, 820, 740, 600 NMR(CDC1 3 , ppm): 0.6-1.9 (11H, m), 2.2 (6H, s), 2.3-2.6 (lH, m, Eliminated by the treatment with D 2 0), 2.35 (2H, s), 3.4-3.8 (2H, m), 4.3-4.7 (2H, m), 4.8-5.1 (2H, d), 5.7-6.0 (2H, m), 6.67 (lH,
  • Example 8 Preparation of 3-methylamino-4-[4- ⁇ 4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide: Yield: 70.7% Melting Point: 87 to 90°C IR(KBr, cm -1 ): 3300, 3120, 2930, 1610, 1570, 1405, 1300, 1150, 1030, 835, 615 NMR(DMSO-d 6 , ppm): 1.1-1.8 (6H, m), 2.05-2.6 (4H, m), 2.9 (2H, s), 3.4 (2H, s), 3.8-4.3 (2H, m), 4.65-5.0 (2H, d), 5.4-5.9 (2H, m), 6.6 (lH, s), 6.7-6.9 (lH, d), 7.5-8.1 (lH, d)
  • Example 9 Preparation of 3-amino-4-[4- ⁇ 4
  • Example 14 Preparation of 3-methylamino-4-[4- ⁇ 4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide: Light Yellow Crystal Yield: 49.3% I R (K B r, cm-1): 3350, 2960, 1640, 1420, 1310, 1165, 1030 NMR(CDCl 3 , ppm): 1.3-1.8 (6H, m), 2.2-2.55 (4H, m), 3.05 (3H, s), 3.35 (2H, s), 4.05-4.3 (2H, d), 4.7-4.95 (2H, d), 5.65-5.85 (2H, m), 6.6 (lH, s), 6.7-6.9 (lH, d), 7.4-7.65 (2H, b, Eliminated by the treatment with D 2 0), 7.8-8.0 (lH, d)
  • Example 30 Preparation of 6-amino-5-[4- ⁇ 4-(1-piperidinomethyl) pyridyl-2-oxy>trans-2-butenylamino]-1,2,4-triazin-3-one: Colorless Crystal Yield: 46.8%
  • Example 32 Preparation of 1-amino-2-[4- ⁇ 6-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobuten-3,4-dione:
  • Example 33 Preparation of 1-methylamino-2-[4- ⁇ 6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino)-1-cyclobuten-3,4-dione: Colorless Crystal Yield: 64.9% Melting Point: 203 to 206°C (d)
  • Example 35 Preparation of 3-methylamino-4-[ 4 - ⁇ 6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-l,2,5-thiadiazole-l-oxide: Light Yellow Crystal Yield: 42.6%
  • IR KB r, cm-1): 3320, 2950, 1610, 1450, 1305, 1260, 1305, 1260, 1160, 1040, 850, 800, .
  • Example 37 Preparation of 3-methylamino-4-[4- ⁇ 6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-betenylaminol-1,2,5-thiadiazole-1,1-dioxide: Light Yellow Crystal Yield: 51.8% Melting Point: 50 to 54°C IR(KBr, cm- 1 ): 3300, 2900, 1630, 1440, 1400, 1300, 1150, 900, 750, 630, 540 NMR(CDCl 3 , ppm): 1.2-1.7 (6H, m), 2.2-2.6 (4H, m), 2.9 (3H, s), 3.4 (2H, s), 3.9-4.2 (2H, m), 4.7-5.0 (2H, m), 5.5-5.9 (2H, m), 6.4-7.8 (3H, m)
  • Example 40 Preparation of 2-methylamino-5-[4- ⁇ 6-(1-piperidinomethyl)pyridyl-2-oxy> - cis-2-butenylaminoJ-1,3,4-thiadiazole: Yield: 45.3% ; Melting Point: 75 to 80°C IR(KBr, cm -1 ): 3250, 2960, 1615, 1455, 1310 NMR(DMSO-d 6 , ppm): 1.35-1.7 (6H, m), 2.3-2.65 (4H, m), 3.2 (3H, s), 3.5 (2H, s), 3.7-4.0 (2H, m), 4.7-4.9 (2H, d), 5.5-5.7 (2H, m), 6.45 (lH, bro, Eliminated by the treatment with D 2 0.)
  • Example 46 Preparation of 3-[4- ⁇ 6-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-6-(3-pyridylmethyl)-1,2,4-triazin-5-one: Yield: 13% Melting Point: 154 to 156°C IR(KBr, cm-1): 3250, 3050, 1600, 1580, 1460, 1310, 1020, 800, 710 NMR(CDC1 3 , ppm): 1.1-1.9 (6H, m), 2.2-2.8 (4H, m), 3.63 (2H, s), 3.84 (2H, s), 3.7-4.4 (2H, m), 4.6-5.1 (2H, m), 5.2-5.9 (2H, m), 6.3-8.6 (7H, m), 7.0-9.0 (2H, bro, Eliminated by the treatment with D 2 0.)
  • Example 47 Preparation of 4-amino-6-[4- ⁇ 6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-2-one: Yield: 60% Melting Point: 214°C IR (K B r, cm -1 ): 3350, 3260, 3070, 2950, 2870, 2800, 1680, 1650, 1610, 1600, 1580, 1540 NMR (DMSO-d 6 , ppm): 1.3-1.6 (6H, m), 2.2-2.5 (4H, m), 3.4 (2H, s), 3.6-3.9 (2H, m), 4.5-4.9 (3H, m), 5.4-5.65 (2H, m), 6.3-7.5 (3H, m)
  • Example 49 Preparation of 6-amino-5-[4- ⁇ 6-(1-piperiaino- methyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-3-one: Yield: 78% Melting Point: 160 to 170°C (d)
  • Example 53 Preparation of 1-[4- ⁇ 4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-2-(2-pyridylmethylamino)-l-cyclobuten-3,4-dione: Colorless Crystal Yield: 79.6% Melting Point: 191 to 195°C IR(KBr, cm -1 ): 3200, 2950, 1800, 1643, 1560, 1480, 1430, 1290, 1163, 1050, 843, 780, 700, 635 .

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Abstract

Pyridyloxy derivatives represented by the general formula:
Figure imga0001
wherein the substituted group Z is either one of the following groups:
Figure imga0002
 were prepared. These derivatives exert antagonism against Histamine H2-receptors and hence are efficacious for the treatments of digestive ulcers.

Description

  • The present invention relates to pyridyloxy derivatives, and more particularly to aminoalkylpyridyloxy derivatives and medically acceptable salts, hydrates and solvates thereof which exert antagonism to histamine H2- receptors and thus have utility in medical treatment of digestive ulcers.
  • It has hitherto been well-known in the art that gastric acid secretion can be controlled by blocking the histamine H2-receptors from the histamine action and that gastric secretion in an animal or a human being can be suppressed by the use of a substance having an antagonism to the histamine H2-receptors. (In this connection, reference should be made to R. W. Brimblecombe et al., J. Int. Med. Res., 3, 86, 1975.)
  • Amongst the known histamine H2-receptor antagonists, particularly well-known is Cimetidine which has been marketed as the first commercially available medicine for treating digestive ulcers.
  • Considerable research has been made to find substances having antagonism to histamine H2.-receptors which are superior to that of Cimetidine, and a variety of heterocyclic compounds were synthesized and the antagonism to histamine H2-receptor thereof were investigated. Japanese Patent Laid-Open Publication Nos. 84867/1984 and 118767/1984 are pertinent references in this connection, and the contents thereof are incorporated herein as part of the specification.
  • The object of this invention is to provide novel substituted aminoalkylpyridyloxy derivatives which exert superior antagonism to histamine H2-receptors to suppress gastric secretion of animals appreciably and which also provide shielding functions to protect the mucous membrane and to promote the secretion of mucus.
  • The compounds provided by the present invention are aminoalkylpyridyloxy derivatives represented by the general formula:
    Figure imgb0001
    wherein X is
    Figure imgb0002
    (wherein Rl and R2 are individually hydrogen atoms or lower alkyl groups having 1 to 6 carbon atoms, or Rl and R2 form, together with the bonded nitrogen atom, a four to eight-membered heterocyclic ring which may have a further substituting group or groups; A is a straight-chain or branched-chain alkylene group having 1 to 6 carbon atoms); and Z is either one of the following groups:
    Figure imgb0003
    Figure imgb0004
    Figure imgb0005
    or
    Figure imgb0006
    wherein R3, R4, R5, R6, R7, R8, R9, R10, Rll, R12, R131 R14, R15, R16, R17 and R18 are individually hydrogen atoms or alkyl groups having 1 to 6 carbon atoms, alkenyl, alkynyl, aralkyl, heterocyclic aryl alkyl groups; or a four to eight-membered heterocyclic group is formed respectively by R3 and R4, R5 and R6, R7 and R8, R10 and Rll, Rl3 and R14, R16 and R17, together with the nitrogen atoms bonded therewith; R12 is a hydrogen atom or an alkyl group havinq 1 to 6 carbon atoms, dialkylamino - alkyl group
    Figure imgb0007
    dialkylaminoalkylbenzyl group
    Figure imgb0008
    or pyridylalkyl group
    Figure imgb0009
    (wherein R19, R20, R21 and R22 are alkyl groups having 1 to 6 carbon atoms; q, r and s indicate integers of 1 to 6);
  • G is a nitrogen or carbon atom, p indicates 0, 1 or 2 and, Q indicates oxygen or sulfur; and medically acceptable salts, hydrates and solvates thereof, and pharmaceutics for digestive ulcers which comprise any of the foregoing as an effective ingredient.
  • The present invention will now be described in detail with reference to preferred embodiments thereof.
  • Initially, examples of the lower alkyl group having 1 to 6 carbon atoms which are included as either one or both of the groups Rl and R2 are methyl, ethyl, n-prpropyl, iso-propyl. n-butyl, s-butyl, t-butyl, n-amyl, and n-hexyl groups.
  • Examples of the hetrocyclic groups formed by the combination of the groups Rl and R2 together with the nitrogen atom bonded therewith are azetidino-, pyrrolidino-, piperidino- and perhydroazepino- groups. These heterocyclic rings may include further substituent groups, such as hydroxyl, methoxy, ethoxy and lower alkyl groups having 1 to 6 carbon atoms.
  • It is preferable that a substituent X in the general formula defined in the claim should combine with pyridyne ring at the 4th or 6th position thereof.
  • Examples of alkylene groups, identified by A, include methylene, ethylene, propylene, iso-propylene and isobutylene.
  • In the group Z contained in the general formula defined in the claim, the groups R3, to R22 include, for example, alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, n-amyl, iso-amyl and n-hexyl; alkenyl groups, such as ethenyl, 2-propenyl, 2-butenyl and 3-butenyl; alkynyl groups, such as 2-propargyl; aralkyl groups, such as 2-dimethylaminomethylbenzyl, 3-dimethylaminomethylbenzyl, 4-dimethylaminomethylbenzyl and 3-methoxybenzyl; heterocyclic aryl alkyl groups, such as 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-furanylmethyl, 2-thiofuranylmethyl, 3-thiofuranylmethyl, 5-diemthylaminomethyl-2-furanylmethyl and 5-dimethylaminomethyl-2-thiofuranylmethyl.
  • Preferred heterocyclic groups, which are formed, respectively, by R3 and R4, R5 and R6, R7 and R8, R10 and Rll, R13 and R14 and, R16 and R17, together with the corresponding nitrogen atoms bonded therewith, are azetidino-, pyrrolidino-, piperidino- and 4-methylpiperazino-rings.
  • The compounds of the invention represented by the general formula (1) can be either in the cis or trans geometrical isomer forms.
  • Illustrative examples of the compounds provided by the invention and represented by the general formula (1) are the following compounds including those specifically referred to in the Examples given hereinafter.
    • l-amino-2-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclonbuten-3,4-dione;
    • 1-methylamino-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 1-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenyl- amino]-2-n-propylamino-1-cyclobuten-3,4-dione;
    • 1-[4-<4-(1-piperidinoethyl)pyridyl-2-Qxy>-cis-2-butenyl- amino]-2-propargylamino-l-cyclebuten-3,4-dione;
    • 1-amino-2-[4-<4-(1-pyrrolidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-l-cyclobuten-3,4-dione;
    • 1-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-2-methylamino-1-cyclobuten-3,4-dione;
    • 1-amino-2-[4-<6-(1-piperidinomethyl)pyridyl-2-Qxy>-trans-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 1-methylamino-2-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 1-amino-2-[4-<6-(1-pyrrolidinomethyl,)pyridyl-2-oxy>-trans 2-butenylamino]-1-cyclobuten-3,4-dione;
    • 1-methylamino-2-[4-<4-(7,-pyrrolidinomethyl)pyridyl-2-oxy>- trans-2-butenylaminol-l-cyclobuten-3,4-dione;
    • 1-n-hexylamino-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 3-amino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole;
    • 3-methylamino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1,2,5-thiadiazole;
    • 3-amino-4-[4-<4-(1-pyrrolidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-l,2,5-thiadiazole;
    • 3-methylamino-4-[4-<4-(1-pyrrolidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1,2,5-thiadiazole;
    • 3-amino-4-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1.2,5-thiadiazole;
    • 3-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenyl- amino>-4-methylamino-1,2,5-thiadiazole;
    • 3-amino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-1,2,5-thiadiazole;
    • 3-methylamino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-l,2,5-thiadiazole;
    • 3-amino-4-<4-(4-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-1,2,5-thiadiazole;
    • 3-<4-(4-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenyl- amino>-4-methylamino -1,2,5-thiadiazole;
    • 3-amino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide;
    • 3-methylamino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide;
    • 3-amino-4-[4-<4-(l-pyrrolidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide;
    • 3-methylamino-4-[4-<4-(1-pyrrolidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide;
    • 3-amino-4-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole-l-oxide;
    • 3-amino-4-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-1,2,5-thiadiazole-1-oxide;
    • 3-methylamino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-1,2,5-thiadiazole-1-oxide;
    • 3-amino-4-<4-(4-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-1,2,5-thiadiazole-1-oxide;
    • 3-<4-(4-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-4-methylamino-1,2,5-thiadiazole-1-oxide;
    • 3-amino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-methylamino-4-[4-<4-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-amino-4-[4-<4-(1-pyrrolidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-methylamino-4-[4-<4-(l-pyrrolidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-amino-4-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole-1,1-dioxide;
    • 3-amino-4-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-methylamino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-amino-4-<4-(4-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-1,2,5-thiadiazole-1,1-dioxide;
    • 3-<4-(4-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-4-methylamino-1,2,5-thiadiazole-1,1-dioxide;
    • 2-amino-5-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino)-1,3,4-thiadiazole;
    • 2-methylamino-5-[4-<4-(l-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,3,4-thiadiazole;
    • 2-amino-5-[4-<4-(l-pyrrolidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-l,3,4-thiadiazole;
    • 2-methylamino-5-[4-<4-(l-pyrrolidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,3,4-thiadiazole;
    • 2-amino-5-[4-<4-(dimethylaminomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1,3,4-thiadiazole;
    • 2-[4-<4-(dimethylaminomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-5-methylamino-1,3,4-thiadiazole;
    • 2-amino-5-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy->- trans-2-butenylamino]-1,3,4-thiadiazole;
    • 2-methylamino-5-[4-<4-(l-piperidinomethyl)pyidyl-2- oxy>-trans-2-butenylamino]-1,3,4-thiadiazole;
    • 2-ethylamino-5-[4-<4-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,3,4-thiadiazole;
    • 2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-5-n-propylamino-1,3,4-thiadiazole;
    • 2-n-hexylamino-5-[4-<4-(l-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,3,4-thiadiazole;
    • 3-amino-l-methyl-5-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-1,2,4-triazole;
    • 3-amino-l-methyl-5-[4-<4-(l-pyrrolidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-lH-l,2,4-triazole;
    • 3-amino-l-methyl-5-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-1H-1,2,4-triazole;
    • 3-amino-1-ethyl-5- [4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-1,2,4-triazole;
    • 1-methyl-3-methylamino-5-[4-<4-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1H-1,2,4-triazole;
    • 5-dimethylaminomethyl-2- [4-<4-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 5-dimethylaminomethyl-2-[4-<4-(1-pyrrolidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 5-dimethylaminomethyl-2-[4-<4-(dimethylaminomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 5-dimethylaminomethyl-2-[4-<4-(1-piperdinomethyl) pyridyl-2-oxy>-trans-2-butenylamino]-1H-pyrimidin-4-one;
    • 2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-5-(3-pyridylmethyl)-1H-pyrimidin-4-one;
    • 5-(3-pyridylmethyl)-2-[4-<4-(l-pyrrolidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 2-[4-<4-(dimethylaminomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-5-(3-pyridylmethyl)-1H-pyrimidin-4-one;
    • 5-(3-dimethylaminomethylbenzyl)-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 5-(3-dimethylaminomethylbenzyl)-2-[4-<4-(1-pyrrolidino- methyl)pyridyl-2-oxy>-cis-2-butenylamino]-lH-pyrimidin-4-one;
    • 5-(3-dimethylaminomethylbenzyl)-2-[4-<4-(dimethylaminomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-lH-pyrimidin-4-one;
    • 5-(3-dimethylaminomethylbenzyl)-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-lH-pyrimidin-4-one;
    • 5-[5-(1,3-benzodioxolyl)methyl]-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-pyrimidin-4-one;
    • 3-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-6-(3-pyridynomethyl)-1,2,4-triazin-5-one;
    • 6-(3-pyridynomethyl)-3-[4-<4-(l-pyrrolidinomethyl) pyridyl-2-oxy>-cis-2-butenylaminol-1,2,4-triazin-5-one;
    • 3-[4-<4-(dimethylaminomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-6-(3-pyridynomethyl)-1,2,4-trazin-5-one;
    • 3-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-6-(3-pyridynomethyl)-1,2,4-triazin-5-one;
    • 6-(3-dimethylaminomethyl)-3-[4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-5-one;
    • 6-(3-dimethylaminomethyl)-3-[4-<4-(1-pyrrolidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-5-one;
    • 4-amino-6-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-2-one;
    • 4-methylamino-6-[4-<4-(l-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1H-pyrimidin-2-one;
    • 4-amino-6-[4-<4-(1-pyrrolidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1H-pyrimidin-2-one:
    • 4-methylamino-6-[4-<-(1-pyrrolidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-lH-pyrimidin-2-one;
    • 4-amino-6-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylaminoj-lH-pyrimidin-2-one;
    • 4-dimethylamino-6-[4-<4-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1H-pyrimidin-2-one;
    • 6-amino-5-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-3-one;
    • 6-methylamino-5-[4-<4-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,2,4-triazin-3-one;
    • 6-amino-5-[4-<4-(dimethylaminomethy)pyridyl-2-oxy>- cis-2-butenylamino]-l,2,4-triazin-3-one;
    • 5- [4-<4-(1-piperidinomethyl)pyridxl-2-oxy>-cis-2- 2-butenylamino]-6-propylamino-l,2,4-triazin-3-one;
    • 6-amino-2-methyl-5-[4-<4-(1-piperidinomethle)phridyl-2-oxy>-cis-2-butenylamino]-1,2,4-traizin-3-one;
    • 2-butyl-6-methylamino-5-[4-<4-(1-piperidinomethy)pyridyl-2-oxy>-trans-2-butenylamino]-1,2,4-triazin-3-one;
    • 1-amino-2-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 1-methylamino-2-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1-cycloten-3,4-dione;
    • 1-(4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-2-n-propylamino-1-cyclobuten-3,4-dione;
    • 1- [4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-2-propargylamino-1-cyclobuten-3,4-dione;
    • 1-amino-2-(4-<6-(1-pyrrolidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 1-methylamino-2-(4-<6-(1-pyrrolidinomethyl)pyridyl-2- oxy>-trans-2-butenylamino]-1-cyclobuten-3,4-dione;
    • l-amino-2-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 1-methylamino-2-[4-<6-(1-piperidinomethyl)pyridyl-2- oxy>-trans-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 1-amino-2-[4-<6-(1-pyrrolidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-l-cyclobuten-3,4-dione;
    • 1-methylamino-2-[4-<6-(1-pyrrolidinomethyl)pyridyl-2- oxy>-trans-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 1-n-hexylamino-2-[4-<6-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1-cyclobuten-3,4-dione;
    • 3-amino-4-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1,2,5-thiadiazole;
    • 3-methylamino-4-[4-<6-(piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-l,2,5-thiadiazole;
    • 3-amino-4-[4-<6-(l-pyrrolidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1,2,5-thiadiazole;
    • 3-methylamino-4-[4-<6-(l-pyrrolidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,2,5-thiadiazole;
    • 3-amino-4-<4-(6-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole;
    • 3-<4-(6-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-4-methylamino-l,2,5-thiadiazole;
    • 3-amino-4-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-1,2,5-thiadiazole;
    • 3-methylamino-4-[4-<6-(1-piperidinomethyl)pyridyl-2- oxy>-trans-2-butenylamino]-1,2,5-thiadiazole;
    • 3-amino-4-<4-(6-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-1,2,5-thiadiazole;
    • 3-<4-(6-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-4-methylamino-1,2,5-thiadiazole;
    • 3-amino-4-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide;
    • 3-methylamino-4-[4-<6-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-l,2,5-thiadiazole-l-oxide;
    • 3-amino-4-[4-<6-(1-pyrrolidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-l-oxide;
    • 3-methylamino-4-[4-<6-(1-pyrrolidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide;
    • 3-amino-4-<4-(6-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole-1-oxide;
    • 3-amino-4-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-1,2,5-thiadiazole-1-oxide;
    • 3-methylamino-4-[4-<6-(1-piperidinomethyl)pyridyl-2- oxy>-trans-2-butenylamxno]-1,2,5-thiadiazole-1-oxide;
    • 3-amino-4-<4-(6-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-1,2,5-thiadiazole-1-oxide;
    • 3-<4-(6-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-4-methylamino-1,2,5-thiadiazole-1-oxide;
    • 3-amino-4-[4-<6-(1-piperidinomethyl)gyridyl-2-oxy>- cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-amino-4-[4-<6-(1-piperidipomethyl)pycidyl-2-oxy>- cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-methylamino-4-[4-<6-(1-pyrrolidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-amino-4-<4-(6-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole-1,1-dioxide;
    • 3-amino-4-(4-<6-(1-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-methylamino-4-[4-<6-(l-piperidinomethyl)pyridyl-2- oxy>-trans-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide;
    • 3-amino-4-<4-(6-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-1,2,5-thiadiazole-1,1-dioxide;
    • 3-<4-(6-dimethylaminomethylpyridyl-2-oxy)-trans-2-butenylamino>-4-methylamino-1,2,5-thiadiazole-1,1-dioxide;
    • 2-amino-5-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1,3,4-thiadiazole;
    • 2-methylamino-5-(4-<6-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1,3,4-thiadiazole;
    • 2-amino-5-[4-<6-(dimethylaminomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1,3,4-thiadiazole;
    • 2-[4-<6-(dimethylaminomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-5-methylamino-1,3,4-thiadiazole;
    • 2-amino-5-(4-<6-(1-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-1,3,4-thiadiazole;
    • 2-methylamino-5-[4-<6-(l-piperidinomethyl)pyridyl-2- oxy>-trans-2-butenylamino]-1,3,4-thiadiazole;
    • 2-ethylamino-S-[4-<6-(l-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-l,3,4-thiadiazole;
    • 2-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-5-n-propylamino-1,3,4-thiadiazole;
    • 2-n-hexylamino-5-[4-<6-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1,3,4-thaidiazole;
    • 3-amino-l-methyl-5-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-1,2,4-triazole;
    • 3-amino-1-methyl-5-[4-<6-(1-pyrrolidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1H-1,2,4-triazole;
    • 3-amino-l-methyl-5-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-lH-l,2,4-triazole;
    • 3-amino-1-ethyl-5-[4-<6-(piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1H-1,2,4-triazole;
    • 1-methyl-3-methylamino-5-[4-<6-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylaminol-1H-1,2,4-traizole;
    • 5-dimethylaminomethyl-2-(4-<6-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 5-dimethylaminomethyl-2-[4-<6-(l-pyrrolidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 5-dimethylaminomethyl-2-[4-<6-(dimethylaminomethyl) pyridyl-2-oxy>-cis-2-butenylaminol-lH-pyrimidin-4-one;
    • 5-dimethylaminomethyl-2-[4-<6-(1-piperidinomethyl) pyridyl-2-oxy>-trans-2-butenylamino]-1H-pyrimidin-4-one;
    • 2-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-5-(3-pyridylmethyl)-1H-pyrimidin-4-one;
    • 5-(3-pyridylmethyl)-2-[4-<6-(1-pyrrolidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-lH-pyrimidin-4-one;
    • 2-[4-<6-(dimethylaminomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-5-(3-pyridylmethyl)-lH-pyrimidin-4-one;
    • 5-(3-dimethylaminomethylbenzyl)-2-[4-<6-
    • (1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 5-(3-dimethylaminomethylbenzyl)-2-[4-<6-(l-pyrrolidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 5-(3-dimethylaminomethylbenzyl)-2-[4-<6-(dimethylaminomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one;
    • 3-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-6-(3-pyridylmethyl)-2H-1,2,4-triazin-5-one;
    • 6-(3-pyridylmethyl)-3-[4-<6-(1-pyrrolidinomethyl) pyridyl-2-oxy>-cis-2-butenylainino]-2H-1,2,4-triazin-5-one;
    • 3- [4- <6- (dimethylaminomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-6-(3-pyridylmethyl)-2H-1,2,4-triazin-5-one;
    • 3-[4-<5-(1-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-6-(3-pyridylmethyl)-2H-1,2,4-triazin-5-one;
    • 6-(3-dimethylaminomethyl)-3-[4-<6-(l-pyrrolidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-2H-1,2,4-triazin-5-one;
    • 4-amino-6-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1H-pyrimidin-2-one;
    • 4-methylamino-6-[4-<6-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1H-pyrimidin-2-one;
    • 4-amino-6-[4-<6-(1-pyrrolidinomethyl)pyridyl-2-oxy>- cis-2-butenylaminol-1H-pyrimidin-2-one;
    • 6-[4-<6-(dimethylaminomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-4-methylamino-1H-pyrimidin-2-one;
    • 4-amino-6-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-1H-pyrimidin-2-one;
    • 4-dimethylamino-6-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-2-one;
    • 6-amino-5-(4-<6-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-2H-1,2,4-triazin-3-one;
    • 6-methylaming-5-(4-<6-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino)-2H-1,2,4-triazin-3-one;
    • 6-amino-5-[4-<6-(dimethylaminomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-2H-1,2,4-triazin-3-one;
    • 5-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylaminoj-6-n-propylamino-2H-1,2,4-triazin-3-one;
    • 6-amino-2-methyl-5-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-2H-1,2,4-triazin-3-one; and
    • 2-butyl-6-methylamino-5-(4-<6-(1-piperidinomethyl) pyridyl-2-oxy>-trans-2-butenylamino]-2H-1,2,4-traizin-3-one.
    • 1-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>cis-2-butenylamino]-2-(3-pyridylmethylamino)-1-cyclobuten-3,4-dione;
    • 1-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>cis-2-butenylaminoj-2-(4-pyridylmethylamino)-l-cyclobuten-3,4-dione;
    • 1-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>cis-2-butenylamino]-2-(3-pyridylmethylamino)-l-cyclobuten-3,4-dione;
    • 1-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>cis-2-butenylamino]-2-(4-pyridylmethylamino)-1-cyclobuten-3,4-dione;
  • The compounds of the invention represented by the general furmula (1) and the salts thereof can be prepared, depending on the substituents Z included therein, through the following different processes.
  • (A) Compounds wherein Z is
    Figure imgb0010
    Figure imgb0011
    Figure imgb0012
  • In the reaction equations set forth above, X, R3 and R4 are the groups as described hereinbefore and defined in the claims; R20 is a lower alkyl, preferably methyl or ethyl; and E is -0- or -S-, preferably -O-.
  • The first and second steps can be carried out separately, but it- is preferable that they be carried out sequentially without interruption. It is preferred that both of the starting materials be used in the equivalent molar ratio in the first step, whereas in the second step it is preferred that amine
    Figure imgb0013
    be used in an excess amount, for example, in an amount of two to five times the moles of the resultant product of the first step.
  • Both steps can be carried out without using a solvent or may be carried out in an inert organic solvent such as methanol, ethanol, propanol, acetonitrile or chloroform. The reaction temperature ranges generally from -10°C to the boiling point of the solvent used, the boiling points of the usable solvents ranging generally from 50°C to 150°C, and the preferable temperature range is from room temperature to 80oC. The time required for the completion of reaction varies depending on the reaction temperature, and both reactions can be completed within 30 minutes to 24 hours.
  • The pyridyloxybutenylamine derivative used in the first step is a novel compound and can be prepared, for example, by the following process:
    Figure imgb0014
    wherein X is a group as described hereinbefore and defined in the claims, Hal is a halogen atom such as chlorine, bromine, iodine and fluorine, preferably chlorine or bromine.
  • On the other hand, one of the compounds represented by the formula:
    Figure imgb0015
    i.e. the compound
    Figure imgb0016
    can be prepared by the process disclosed by Sidney Cohenet et al, in J. Am. Chem. Soc., 88 (7), 1533 (1966).
  • (B) Compounds wherein Z is
    Figure imgb0017
    Figure imgb0018
    Figure imgb0019
  • In the reaction equations set forth above, X, R5 and R6 are the groups as described hereinbefore and defined in the claims; R30 is a lower alkyl, preferably methyl or ethyl; and F indicates sulfur (-S-) or oxygen (-0-).
  • The compounds used in the first step and represented by the foumula:
    Figure imgb0020
    are known compounds, and 3,4-dimethoxy―1,2,5-thiaziazole
    Figure imgb0021
  • (p = 0) can be prepared by a process reported by A.P. Komin et al. in J. Org. Chem., 40, 2749 (1975) or a modified process thereof, and 3,4-dimethoxy-1,2,5-thiaziazole-1-oxide
    Figure imgb0022
  • (p = 1) can be prepared by a process described in Japanese Patent Laid-Open Publication No. 40675/1981 or by a modified process thereof, and 3,4-dimethoxy-1,2,5-thiaziazole-1,1-dioxide
    Figure imgb0023
  • (p = 2) can be prepared by a process described in R.Y. Wen et al, J. Org. Chem., 40, 2743(1975) or a modified process thereof.
  • The first step set forth hereinabove can be carried out, for example, by reacting one mole of a derivative of 4- <(3-dialkylaminoalkyl)pyridyl-2-oxy>-2-butenylamine with one to three moles of 3,4-dimenthoxy-l,2,5-thiadiazole, 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide, or 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide in the absence of a solvent or in an inert organic solvent (preferably a lower alcohol such as methanol, ehtanol or propanol, or acetonitrile or chloroform) at a reaction temperature of from -5°C to 100oC, preferably from 0°C to 30°C under agitation. The reaction is completed within 30 minutes to 24 hours, and the end of the reaction may be checked by means of T.L.C.(thin layer chromatography).
  • The reaction of the first step may be continued into the reaction of the second step in a continuous operational sequence. Alternatively, the second step operation may be carried out after refining the resultant product of the first step, for example, by means of column chromatography.
  • The second step operation is carried out by dissolving the resultant product of the first step in an inert organic solvent followed by addition of an amine compound represented by the formula:
    Figure imgb0024
    2 to 10 moles of amine, relative to one mole of the resultant product of the first step, are used; and the second step is carried out generally at a reaction temperature of from -lOoC to 100oC, preferably from 0°C to 30°C. The reaction is completed within 30 minutes to 24 hours.
  • Further, a compound represented by the formula:
    Figure imgb0025
    can be prepared by the following process.
  • The resultant product of the second step, for instance, 3-amino-4-<4-(4-dialkylaminoalkylpyridyl-2-oxy)-2-butenylamino>-1,2,5-thiaziazole-1-oxide;
    Figure imgb0026
    Figure imgb0027
    can be treated with a mineral acid (for example hydrochloric acid) to obtain tetrahydrochloride of N- 4-(4-dialkyl- aminoalkylpyridyl-2-oxy)-2-butenyl ethanediimidamide. Thereafter, the product can be reacted with 1 to 10 moles of sulfur monochloride or N,N'-thiobisphthalimide, relative to one mole of the resultant product to convert it into 3-<4-(4-dialkylaminoalkypyridyl-2-oxy)-2-butenylamino>-4-amino-1,2,5-thiadiazole.
  • Aside from the aforementioned process, the same product can be prepared through the following sequential reactions:
    Figure imgb0028
    Figure imgb0029
    wherein X, R5 and R6 are the same as defined above, and R40 indicates a lower alkyl group.
  • (C) Compounds wherein Z is a group represented by:
    Figure imgb0030
  • Such a compound can be prepared through the following reaction:
    Figure imgb0031
  • Alternatively, such a compound can be prepared by the process including the following first and second steps:
    Figure imgb0032
    Figure imgb0033
    wherein X, R7, R8 and Hal are the same as defined above.
  • Although the latter process has a larger number of steps, it is generally favored because of decreased byproducts and increased yield.
  • 2,5-dihalogeno-l,3,4-thiaziazole used in the first step can be prepared by a process described in R. Stolle et al, J. Prakt. Chem., 122, 289(1929).
  • The first step can be carried out by reacting one mole of an amine derivative with one to three moles of 2,5-dihalogeno-l,3,4-thiaziazole in the absence of a solvent or in an inert organic solvent (preferably methanol, ethanol, propanol, DMF, DMSO) at a temperature of from 50 to 200°C.
  • In the second step, 2 to 10 moles of an amine compound represented by the formula:
    Figure imgb0034
    , relative to one mole of the resultant product of the first step, is used. When a low boiling point amine is used, the reaction can be carried out by heating in a bombenroll or an autoclave at a temperature of higher than the boiling point. It is suitable to use an alcohol. as the solvent, and the reaction temperature ranges from 50°C to 200°C, preferably from 70°C to 100°C.
  • (D) Compounds wherein Z is
    Figure imgb0035
    First Step:
    Figure imgb0036
  • Second Step:
    Figure imgb0037
    wherein X and R9 are the same as defined above and R50 is a lower alkyl, preferably methyl.
  • The first step is carried out by reacting starting materials in equivalent moles in the presence of an inert solvent, optionally under heating. The reaction is completed within 20 minutes to 24 hours, and it is preferred that the reaction be carried out at room temperature within 2 to 6 hours.
  • The second step is carried out by reacting the resultant product of the first step with a hydrazine derivative in an organic solvent such as methanol, ehtanol or propanol, and the molar ratio of the hydrazine derivative to the product of the first step is in the range from 1:1 to 10:1 preferably from 1.5:1 to 3:1. The reaction is completed within 30 minutes to 24 hours at a reaction temperature of from room temperature to 150°C, and is preferably carried out at the boiling point of a lower alcohol such as methanol and ethanol within 5 to 10 hours.
  • Both R10 and Rll of the product prepared above are hydrogen atoms. Derivatives wherein R10 and Rll are other than hydrog.en atoms can be prepared by reacting the product with a compound having an active elimination group such as haloalkyl.
  • N-cyanodialkyldithio-imido-carbonate used in the reaction of the first step is a known compound and can be prepared by a method described in Japanese Patent Publication No. 46-26482.
  • (E) Compounds wherein Z is
    Figure imgb0038
  • Such a compound can be prepared through the following reaction.
    Figure imgb0039
     wherein X, G and R12 are the same as refined above; and B is R60S-(R60 is a lower alkyl, preferably methyl) or nitroamine (-NH-N02).
  • When B is a methylthio group, the above reaction can be carried out by melting without a solvent at about 150°C or by refluxing in pyridine.
  • Further, when B is nitroamine, the above reaction can be carried out by refluxing in an inert solvent such as ethanol and pyridine.
  • A part of the above pyrimidone derivates (G being -CH=) and triazine derivatives (G being -N=) are known compounds and can be prepared by, for example, methods described in Japanese Patent Laid-Open Publication Nos. 53- ll6392 and 55-11583, or by a modified mehtod thereof, which should be obvious to those skilled in the art.
  • (F) Compounds wherein Z in
    Figure imgb0040
  • Such a compound can be prepared through the following reaction.
    Figure imgb0041
  • Wherein X, R13 and R14 are the same as defined above; and D is a halogen atom (chlorine, bromine or iodine) or a methylthio group.
  • The compound used in the above reaction and represented by the following formula:
    Figure imgb0042
    , for example hydrochloride of 6-amino-4-chloro-2(lH)-pyrimidone, can be prepared by the process reported by Wolfgang Pfleiderane et al, in Ann., 657, 149 (1962). The reaction can proceed in a solvent or without using any solvent. Usable solvents include, for example, methanol, ethanol, water, DMF and DMSO. The reaction can proceed at 50°C to 150°C for 5 minutes to 24 hours under agitation.
  • (G) Compounds wherein Z is
    Figure imgb0043
  • Such a compound can be prepared through the following reaction.
    Figure imgb0044
  • Wherein X, R16, R17 and R18 are the same as defined above; and L is R70S-(R70 is an alkyl, preferably methyl) or a hologen atom (chlorine, bromine, or iodine).
  • The reaction set forth above can proceed at 50°C to 150°C in an inert organic solvent or without using any solvent. Examples of the inert solvents include alcohols, preferably methanol, ethanol and propanol, and the reaction may proceed preferably under reflux of such a solvent.
  • The compounds represented by the formula:
    Figure imgb0045
    can be prepared by the process reported by C. C. Tzeng et al, in J. Org. Chem., 26, 1118 (1961), or by a modified process thereof, which should be obvious to those having ordinary skill in the art.
    • Pharmaceutical Efficacies of the Compounds of the Invention:
  • Some compounds of this invention were tested and compared with Cimetidine which has been widely used for clinical applications as a medicine for digestive ulcers as having an antagonistic function on the histamine H2-receptor.
    • A) Inhibition Effect on Gastric Acid Secretion Induced by Histamine in Pylorus Liqated Rat
  • The test was conducted by an improved method based on that reported by Watanabe et al., in "Pharmacometrics", Vol. 3, No. (1), pages 7 to 14 (1969).
  • A male Wistar rat having a body weight of about 160 g and which had not fed for 24 hours was anesthetized by an intraperitoneal dose of 1.2 g/kg of urethane. After ligating of pylorus and esophagus, the gaster anterior was incised and fitting with a double polyethylene cannula. The wall of the stomach was rinsed with 5 mℓ pf saline at 30 minutes intervals, and the quantity of gastric acid contained in each rinsing solution was measured by titration.
  • The basal acid secretion was initially measured three times, and then 0.2 mg/kg of each of the compounds of this invention was administered subcutaneously and 3 mg/kg of histamine was administered subcutaneously after the lapse of an additional 30 minutes.
  • The quantity of gastric acid secreted after the operation was measured continuously for 3 hours. Within that measurement interval, three time points at which the increase in acid secretion reached a maximum level were selected, and the average quantity of gastric acid secreted at those time points was taken as the increase in acid secretion, which was compared with the increase in acid secretion of the control group to calculate the percent inhibition for secretion of gastric acid (Table 1).
    Figure imgb0046
  • (The result was shown as the average value of five runs.)
  • Each of the compounds having strong inhibition effects on the secretion of gastric acid was administered to each rat intraduodenally 30 minutes before the subcutaneous injection of histamine to find the amount to be administered for suppressing gastric acid secretion by 50% (ED50). The results are shown in Table 2-1 and 2-2.
    • B) Determination of Inhibitory Effect on Histamine H2 Receptor in isolated Guinea Pig Atria
  • A male Hartley guinea pig having a body weight of about 400 g was killed by cervical dislocation, and the atrium thereof was isolated and was suspended in an organ bath containing 50 m of a modified Ringer solution and subjected to a tension of 1 g. The number of heart beats under such condition was recorded using a polygraph.
  • Initially, from 1 x 10-7 mol to 3 x 10-4 mol of histamine was allowed to act accumulatively to depict the curve of the dosage-reaction relationship. Likewise, the curve of the dosage of histamine-reaction relationship was depicted in the presence of 5 x 10-7 mol to 1 x 10-6 mol of the test sample which was injected 3 minutes before. The negative logarithm (pA2) of the molar concentration of the test sample required for moving the curve obtained by single administration of histamine parallel to the right side by a two-times concentration was calculated.
  • The results are shown in Table 1.
    • C) Acute Toxicity Test
  • Male ddv mice each having a body weight of about 22 g and which had not eaten for 8 hours were orally dosed with the test samples, and the general symptoms and fatalities were observed from the time immediately following the administration to 14 days after the administration.
  • The median lethal dose ,(LD50) was calculated in accordance with the Litchfield and Wilcoxon Method.
  • The results are shown in Table 3.
    Figure imgb0047
    Figure imgb0048
    Figure imgb0049
    Figure imgb0050
    Figure imgb0051
  • As will be clearly seen from Table 1, the inhibitive actions of the respective compounds, prepared by Examples of the invention and administered subcutaneously on gastric acid secretion induced by histamine were greater than that of Cimetidine. The antagonistic actions against Histamine H2- receptor of the compounds of this invention were comparable with or superior to that of Cimetidine, when tested using isolated right atria of guinea pigs. Particularly, the antagonistic actions of the compound of example 15 were strong.
  • Another characteristic effect of the compound of this invention that was ascertained is that the inhibitory effect on gastric acid secretion by the intraduodenal administration, which is similar to oral administration, was extremely high. For instance, as shown in Tables 2-1, and 2-2, from their ED50 values, the compounds prepared, respectively, by Examples 1, 2, 4, 17, 25, 30, 31, 32 and 36 were about 46.6, 25.9, 63.6, 50.0, 50.0, 26.9, 25.0, 32.8 and 41.0 times more effective than the ED50 value of Cimetidine.
  • The acute toxicity tests conducted by administering the compounds to mice orally revealed that the compounds of examples 22 and 29 had lower LD50 values than that of Cimetidine.
  • Other tested compounds had the LD50 values of more than 1500 mg/kg, showing that the toxicities thereof were low.
  • Accordingly, it should be appreciated that the compounds of this invention have remarkable utility when used as anti-pectic ulcer drugs, since they exhibit powerful inhibitory effects against Histamine H2-receptor and potent suppression effects on gastric acid secretion and yet are less toxic.
  • The compounds of this invention may be used either in the free form or in the form of acid addition salts thereof. Pharmaceutically acceptable acid addition salts of the compounds of this invention are, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate and organic acid addition salts such as acetate, propionate, citrate, malate, fumarate, methanesulfonate and so forth.
    • EXAMPLES OF THE INVENTION
  • Example 1: Preparation of 1-amino-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobuten-3,4-dione:
    • (A) 4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine: 12 grams of 60% sodium hydride was dispersed in 481 ml of absolute tetrahydrofuran, and slowly added with 24 g (0.276 mol) of 4-amino-cis-2-buten-l-ol. The reaction solution was stirred at 50°C for 30 minutes followed by cooling, and then slowly added with 44 g (0.173 mol) of 2-bromo-4-(1-piperidinomethyl) pyridine (prepared by applying the method described in Japanese Patent Laid-Open Publication No. 58-170779) in 40 ml of tetrahydrofuran and the resultant mixture was refluxed and stirred for 40 hours. The solvent was distilled off after the completion of the reaction, and the residue was added with 200 ml of water and extracted with 200 ml of dichloromethane four times. The solvent was distilled off after drying an organic solvent layer with magnesium sulfate anhydrous, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of methanol-ethyl acetate (1:4). As a result, 38.7 g (85.9%) of the captioned compound was obtained as a light brown oily product.
  • IR(neat, cm-1): 3400, 3300, 2950, 1620, 1563, 1480, 1420, 1315, 1040, 830 NMR(CDCl3, ppm): 1.2-1.9 (6H, m), 2.1-2.6 (4H, m), 2.9 (2H, s), 3.2-3.7 (4H, m), 4.7-5.0 (2H, d), 5.6-5.9 (2H, t), 6.65 (1H, s), 6.7-6.9 (1H, d), 7.9-8.1 (1H, d).
  • (B) 1-methoxy-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-1-cyclobuten-3, 4-dione:
    • 1.42 grams (0.01 mol) of dimethyl squalate (prepared by the process reported by Sideny Cohen et al, in J. Amer. Chem. Soc., Vol 88, 1533 (1966)) was dissolved in 50 ml of absolute methanol and cooled at 5°C. Then a solution of 2.61 grams (0.01 mol) of 4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamine which was prepared by the method described in example 1-(A) in 20 ml of absolute methanol was dropped into the dimethyl squalate solution obtained above at 5°C of solution temperature, with stirring, and was stirred at room temperature for an additional 6 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column to purify the same, followed by elution with a mixed solution of ethyl acetate : methanol=4:1. As a result, 3.4 g (Yield: 91.6%) of the captioned compound was obtained as a light yellow oily product.
  • IR(neat, cm-1): 3250, 2950, 1810, 1720, 1620, 1405, 1040, 1000, 925, 830, 785 NMR(CDCl3, ppm): 1.1-1.8 (6H, m), 2.1-2.6 (4H, m), 3.35 (2H, s), 4.0-4.5 (2H, m), 4.3 (3H, s), 4.7-5.0 (2H, d), 4.9-5.5 (2H, m), 6.6 (1H, s), 6.7-6.9 (lH, d), 7.8-8.2 (lH, d)
  • (C) 1-amino-2-(4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobuten-3, 4-dione:
    • 1.2 grams (3.2 m mol) of 1-methoxy-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobuten-3,4-dione obtained in example 1-(B) was dissolved in 25 ml of absolute methanol to obtain a solution through which dry ammonia gas was passed at 5°C of reaction temperature for 20 minutes, and then the solution was stirred at room temperature for an additional 2 hours.
  • The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column to purify the same, followed by elution with a mixed solution of ethyl acetate and methanol (4:1) and recrystallization from methanol. As a result, 0.75 g (Yield: 65.2%) of the captioned compound was obtained as a colorless crystal having a melting point of 225 to 230°C, at which temperature it decomposed.
  • IR(KBr, cm-1): 3110, 2950, 1810, 1650, 1550, 1435, 1400, 1360, 1150, 1030, 640 NMR(CDC13, ppm): 1.2-1.8 (6H, m), 2.1-2.6 (4H, m), 3.3 (2H, s), 4.1-4.5 (2H, m), 4.8-5.1 (2H, d), 5.5-5.9 (2H, m), 6.6 (lH, s), 6.7-6.9 (lH, d), 7.0-7.5 (2H, m, Eliminated by the D20 treatment), 7.8-8.1 (lH, d)
  • Example 2: Preparation of 1-methylamino-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylaminol-1-cyclobuten-3,4-dione:
    Figure imgb0052
    Yield: 54.3% Melting Point: 207 to 210°C (d) IR(KBr, cm-1): 3200, 2950, 1805, 1640, 1570, 1400, 1290, 1160, 1040, 835, 740, 600 NMR(DMSO-d6/CDCl3, ppm): 1.2-1.9 (6H, m), 2.1-2.7 (4H, m), 3.15 (3H, s), 3.35 (2H, s), 4.1-4.6 (2H, m), 4.7-5.1 (2H, m), 5.5-6.0 (2H, m), 6.65 (lH, s), 6.7-6.9 (lH, d), 7.0-7.6 (lH, m, Eliminated by the treatment with D20), 7.9-8.3 (1H, d)
  • Example 3: Preparation of 1-amino-2-<4-(6-dimethylaminomethyl- pyridyl-2-oxy)-cis-2-butenylamino>-l-cyclobuten-3,4-dione: (A) 4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamine: In accordance with the procedure of example 1-(A) but using 37.2 grams (0.173 mol) of 2-bromo-4-dimethylaminomethylpyridine in place of 44 grams of 2-bromo-4-(1-piperidinomethyl)pyridine, there was obtained 27.1 g (Yield: 74.2%) of the captioned compound as a light brown oily product.
  • IR(neat, cm-1): 3400, 3200, 2950, 2800, 1660, 1620, .1560, 1410, 1290, 1155, 1020, 820 NMR(CDC13, ppm): 2.05 (2H s, Eliminated by the D20 treatment), 2.2 (6H, s), 3.2-3.7 (4H, m), 4.7-5.1 (2H, d), 5.5-6.0 (2H, t), 6.6 (1H, s), 6.7-6.9 (lH, d), 7.9-8.2 (2H, d)
  • (B) 1-methoxy-2-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamine>-1-cyclobuten-3,4-dione:
  • In accordance with the procedure of example 1-(B) but using 2.11 g (0.01 m mol) of 4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamine in place of 4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine, there was obtained 2.6 g (Yield: 78.5%) of the captioned compound as a light yellow oily product.
  • IR(neat, cm-1): 3250, 2960, 1810, 1715, 1610, 1400, 1315, 1160, 1035, 830, 605 NMR(CDCl3, ppm): 2.25 (6H, s), 3.7-4.2 (2H, m), 4.3 (3H, s), 4.7-5.0 (2H, d), 5.4-6.0 (2H, m), 6.6 (1H, s), 6.7-6.9 (lH, d), 7.8-8.2 (lH, d) (C) 1-amino-2-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1-cyclobuten-3,4-dione:
  • In accordance with the procedure of example 1-(C) but using 1.06 g (3.2 m mol) of 1-methoxy-2-<4-(4-dimethylamino- methylpyridyl-2-oxy)-cis-2-butenylaminoi-1-cyclobuten-3, 4-dione in place of 1-methoxy-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>- cis-2-butenylamino]-l-cyclobuten-3,4-dione, there was obtained 0.71 g (Yield: 70.2%) of the captioned compound in a light yellow crystal form. The melting point of the crystal obtained by additional recrystallization from methanol was 222 to 224oC, at which the crystal decomposed.
  • IR(KBr, cm-1): 3320, 3150, 1810, 1640, 1570, 1310, 1150, 1020, 820, 690, 600 NMR(DMSO-d6, ppm): 2.3 (6H, s), 3.0 (lH, s, Eliminated by the D20 treatment), 3.35 (2H, s), 4.1-4.5 (2H, m), 4.8-5.1 (2H, d), 5.6-6.0 (2H, m), 6.75 (lH, s), 6.9-7.05 (lH, d), 7.3-7.8 (2H, m, Eliminated by the D20 treatment), 8.0-8.2 (lH, d)
  • Example 4: Preparation of 1-methylamino-2-<4-(4-dimethylamino- methylpyridyl-2-oxy)-cis-2-butenylamino>-l-cyclobuten-3,4-dione:
    Figure imgb0053
    Yield: 36.2%
  • Melting Point: 195 to 202°C (Recrystallized from methanol) IR(KBr, cm-1): 3200, 2950, 2800, 1810, 1660, 1570, 1400, 1310, 1290, 1150, 1030, 970, 820, 600 NMR(DMSO-d6, ppm): 2.35 (6H, s), 3.1-3.4 (3H, m), 3.55 (2H, s), 4.8-5.0 (2H, d), 5.5-5.9 (2H, m), 5.8-6.2 (lH, m, Eliminated by the treatment with D2O), 6.67 (lH, s), 6.7-6.9 (1H, d), 7.6-7.9 (lH, m, Eliminated by the treatment with D20), 7.9-8.1 (lH, d)
  • Example 5: Preparation of 1-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-2-n-hexylamino-1-cyclobuten-3,4-dione:
    Figure imgb0054
    Yield: 24.2% Melting Point: 120 to 122°C (Recrystallized from methanol- hexane) IR(KBr, cm-1): 3200, 2950, 1810, 1650, 1580, 1430, 1310, 1150, 1030, 820, 740, 600 NMR(CDC13, ppm): 0.6-1.9 (11H, m), 2.2 (6H, s), 2.3-2.6 (lH, m, Eliminated by the treatment with D20), 2.35 (2H, s), 3.4-3.8 (2H, m), 4.3-4.7 (2H, m), 4.8-5.1 (2H, d), 5.7-6.0 (2H, m), 6.67 (lH, s), 6.7-6.9 (lH, d), 6.6-7.0 (lH, m, Eliminated by the treatment with D2O), 7.1-8.1 (lH, d) Example 6: Preparation of 1-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-2-(2-propargylamino)-l-cyclobuten-3,4-dione:
    Figure imgb0055
    Yield: 57.4%
  • Melting Point: 153 to 155°C (Recrystallized from methanol) IR(KBr, cm-1): 3200, 2900, 2800, 1810, 1160, 1570, 1480, 1420, 1350, 1290, 1140, 1100, 1020, 920, 820, 730, 640 NMR(DMSO-d6, ppm): 2.25 (6H, s), 3.35 (2H, s), 4.2-4.6 (4H, m), 4.8-5.1 (2H, d), 5.6-6.0 (2H, m), 6.67 (lH, s), 6.7-6.95 (lH, d), 7.0-7.6 (2H, b, Eliminated by the treatment with D20), 7.9-8.1 (lH, d)
  • Example 7: Preparation of 3-amino-4-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide:
  • (A) 3-ethoxy-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide: 2.61 grams (0.01 mol) of 4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine (obtained by example 1-(A)) was dissolved in 50 ml of absolute ethanol and added with 1.90 g (0.01 mol) of 3,4-diethoxy-1,2,5-thiadiazole-1- oxide (prepared by applying the method described in Japanese Patent Laid-Open Publication No. 56-40675) followed by agitation at room temperature for 2 hours. The solven.t was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column to purify the same, followed by elution with a mixed solution of ethyl acetate : methanol = 4:1. As a result, 3.34 g (Yield: 82.5%) of the captioned compound was obtained as a colorless oily product.
  • IR(neat, cm-1): 3300, 3000, 1620, 1575, 1440, 1330, 1270, 1130, 1040, 850, 800, 730, 635 NMR(CDCl3, ppm): 1.2-1.9 (9H, m), 2.1-2.7 (4H, m), 3.4 (2H, s), 3.8-4.3 (2H, m), 4.3-4.7 (2H, q), 4.8-5.1 (2H, d), 5.5-6.0 (2H, m), 6.7 (lH, s), 6.7-7.0 (lH, d), 7.8-8.2 (lH, d)
  • (B) 3-amino-4-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide:
  • 2.03 g (5 m mol) of 3-ethoxy-4-[4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide was dissolved in 40 ml of absolute ethanol, added with 2 ml of ethanol solution saturated with ammonia gas, and agitated at room temperature for 30 minutes. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column to purify the same, followed by elution with a mixed solution of ethyl acetate : methanol = 4:1. As a result, 1.37 g (Yield: 72.9%) of the captioned compound was obtained in a colorless crystal form. The melting point of the crystal obtained was 173 to 176°C.
  • IR(KBr, cm-1): 3330, 2950, 2800, 1615, 1580, 1480, 1420, 1350, 1300, 1150, 1040, 820, 620 NMR(DMSO-d6/CDCl3, ppm): 1.1-1.8 (6H, m), 2.05-2.65 (4H, m), 3.3 (2H, s), 3.8-4.3 (2H, d), 4.6-5.1 (2H, d), 5.5-6.0 (2H, m), 6.67 (lH, s), 6.7-7.0 (lH, d), 7.25-8.25 (3H, m, 2H were eliminated by the D20 treatment.)
  • Example 8: Preparation of 3-methylamino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide:
    Figure imgb0056
    Yield: 70.7% Melting Point: 87 to 90°C IR(KBr, cm-1): 3300, 3120, 2930, 1610, 1570, 1405, 1300, 1150, 1030, 835, 615 NMR(DMSO-d6, ppm): 1.1-1.8 (6H, m), 2.05-2.6 (4H, m), 2.9 (2H, s), 3.4 (2H, s), 3.8-4.3 (2H, m), 4.65-5.0 (2H, d), 5.4-5.9 (2H, m), 6.6 (lH, s), 6.7-6.9 (lH, d), 7.5-8.1 (lH, d) Example 9: Preparation of 3-amino-4-[4-<4-(1-piperidinomethyl) pyridyl-2-oxy>-trans-2-butenylamino]-1,2,5-thiadiazole-1-oxide:
  • (A) 4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamine: In accordance with the procedure of example 1-(A) but using 24 grams (0.276 mol) of 4-amino-trans-2-buten-l-ol (bp16: 115 to 116°C) in place of 24 g (0.276 mol) of 4-amino- cis-2-buten-l-ol and starting with 44 g (0.173 mol) of 2-bromo-4-(l-piperidinomethyl)pyridine, there was obtained 32.5 g (Yield 72%) of the captioned compound as a light brown oily product.
  • IR(neat, cm-1): 3400, 2950, 1610, 1560, 1420, 1020 NMR(CDCl3, ppm): 1.1-1.9 (6H, m), 2.1-2.7 (4H, m), 3.1-3.7 (2H, m), 3.37 (2H, s), 4.1-5.0 (2H, m), 5.7-6.1 (2H, m), 6.65 (lH, s), 6.77 (lH, d), 7.95 (lH, d)
  • (B) 3-ethoxy-4-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>- trans-2-butenylamino]-1,2,5-thiadiazole-1-oxide:
    • In accordance with the procedure of example 7-(A) but using 4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamine in place of 4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine, there was obtained 1.50 g (Yield: 80.0%) of the captioned compound in a colorless crystal form.
  • IR(KBr,cm-1): 3200, 2950, 1600, 1420, 1320, 1100, 855, 720, 580, 530 NMR(CDC13, ppm): 1.2-1.6 (3H, t), 1.2-1.8 (6H, m), 2.1-2.7 (4H, m), 3.37; (2H, s), 3.9-4.3 (2H, m), 4.2-4.7 (2H, q), 4.6-4.9 (2H, m), 5.7-6.1 (2H, m), 6.2-6.7 (lH, b, Eliminated by the D20 treatment), 6.6-6.9 (2H, m), 7.8-8.1 (lH, d)
  • (C) 3-amino-4-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-1,2,5-thiadiazole-1-oxide:
    • In accordance with the procedure of example 7-(B) but using 0.81 g (2 m mol) of the compound obtained in example 9-(B), there was obtained 0.46 g (Yield: 61.2%) of the captioned compound in a colorless crystal form. The melting point of the crystal obtained by recrystallization from methanol was 204 to 205°C, at which temperature it decomposed.
  • IR(KBr, cm-1): 3300, 2950, 1680, 1620, 1420, 1050 NMR(DMSO-d6, ppm): 1.1-1.7 (6H, m), 2.0-2.6 (4H, m), 3.34 (2H, s), 3.8-4.2 (2H, m), 4.6-4.9 (2H, m), 5.7-6.0 (2H, m), 6.6 (lH, s), 6.7-6.9 (lH, d), 7.91 (lH, d), 7.5-8.3 (3H, m, Eliminated by the D20 treatment)
  • Example 10: Preparation of 3-methylamino-4-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-trans-2-butenylamino]-1,2,5-thiadiazole-1- oxide:
    Figure imgb0057
  • Yield: 67.5%
  • Melting Point: 100 to 101°C (Recrystallized from methanol) IR(KBr, cm-1): 3320, 2950, 1615, 1580, 1415, 1030 NMR(CDC13, ppm): 1.2-1.9 (6H, m), 2.2-2.6 (4H, m), 2.95 (3H, m), 3.7-4.2 (2H, m), 3.86 (2H, s), 4.6-4.9 (2H, m), 5.7-6.0 (2H, m), 6.6 (lH, s), 6.7-6.9 (lH, d), 7.88 (lH, d), 7.7-8.3 (2H, m, Eliminated by the treatment with D20)
  • Example 11: Preparation of 3-amino-4-<4-(4-dimethylaminomethyl- pyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole-1-oxide:
  • (A) 3-ethoxy-4-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole-1-oxide:
  • In accordance with the procedure of example 7-(A) but using 2.21 g (0.01 mol) of 4-(4-dimethylaminomethylpyridyl-2- oxy)-cis-2-butenylamine (obtained in Example 3-(A)), there was obtained 2.76 g (Yield 78.6%) of the captioned compound as a light yellow oily product.
  • IR(neat, cm-1): 3300, 2950, 1620, 1560, 1400, 1380, 1320, 1250, 1120, 1030, 850, 720, 620, 560 NMR(CDCl3, ppm): 1.3-1.55 (3H, t), 2.25 (6H, s), 3.4 (2H, s), 4.3-4.65 (2H, q), 4.8-5.0 (2H, d), 5.6-5.9 (2H, m), 6.63 (lH, s), 6.7-6.9 (lH, d), 7.2-7.7 (lH, b, Eliminated by the D20 treatment), 7.85-8.0 (lH, d)
  • (B) 3-amino-4-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole-1-oxide:
  • In accordance with the procedure of example 7-(B) but using 0.70 g (2 m mol) of the compound obtained in example 11-(A), there was obtained 0.47 g (Yield: 70.0%) of the captioned compound in a colorless crystal form. The melting point of the crystal obtained by recrystallization from methanol was 55 to 60°C.
  • IR(KBr, cm-1): 3250, 3070, 1610, 1580, 1405, 1290, 1150, 1040, 870, 810, 630 NMR(DMSO-d6/CDC13, ppm): 2.3 (6H, s), 3.45 (2H, s), 4.0-4,3 (2H, d), 4.7-5.1 (2H, d), 5.55-6.1 (2H, m), 6.67 (lH, s), 6.7-7.0 (lH, d), 7.9-8.1 (lH, m)
  • Example 12: Preparation of 3-methylamino-4-<4-(4-dimethyl- aminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole-1-oxide:
    Figure imgb0058
  • Light Yellow Crystal Yield: 67.1% IR(KBr, cm-1): 3330, 3150, 3050, 1620, 1415, 1315, 1295, 1160, 1050, 850, 630, 580, 520 NMR(CDCl3, ppm): 2.3 (6H, s), 3.0 (3H, s), 3.45 (2H, s), 4.1-4.4 (2H, m), 4.8-5.05 (2H, d), 5.7-6.0 (2H, m), 6.7 (lH, s), 6.8-6.95 (lH, d), 7.95-8.15 (lH, d), 8.1-8.6 (lH, b, Eliminated by the treatment with D20)
  • Example 13: Preparation of 3-amino-4-[4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide:
  • (A) 3-ethoxy-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide:
  • 2.0 grams (7.65 m mol) of 4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamine (obtained in example 1-(A)) was dissolved in 50 ml of absolute ethanol, added with 1.6 g (7.76 m mol) of 3,4-diethoxy-1,2,5-thiadiazole-1,1-dioxide (prepared by applying the method disclosed in Japanese Patent Laid-Open Publication No. 56-40675), and agitated at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel chromatograph column to purify the same, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 1.2 g (Yield: 37%) was obtained as an oily product.
  • IR(neat, cm-1): 3370, 2960, 1630, 1420, 1290, 1150 NMR(CDCl3, ppm): 1.0-1.4 (3H, t), 1.3-1.8 (6H, m), 2.2-2.7 (4H, m), 3.6 (2H, s), 3.4-3.9 (2H, q), 4.0-4.3 (2H, d), 4.7-5.0 (2H, d), 5.7-5.9 (2H, m), 6.6-7.0 (2H, m), 7.85-8.1 (lH, d)
  • (B) 3-amino-4-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide:
  • 0.42 g (1 m mol) of a 3-ethoxy product prepared in example 13-(A) was dissolved in 25 ml of ethanol to obtain solution through which dry ammonia gas was passed at 5°C of solution temperature for 20 minutes, followed by agitation at room temperature for an additional 2 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column to purify the same, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 0.22 g (Yield: 56.3%) was obtained in a light yellow crystal form. The melting point of the crystal was 218 to 225oC, at which the crystal decomposed.
  • IR(KBr, cm-1): 3600, 3370, 1640, 1260, 1150 NMR(CMSO-d6, ppm): 1.3-1.7 (6H, m), 2.3-2.6 (4H, m), 3.5 (2H, s), 3.5-3.9 (2H, b, Eliminated by the D20 treatment), 3.9-4.1 (2H, d), 4.7-4.9 (2H, d), 5.5-5.8 (2H, m), 6.6 (lH, s), 6.7-6.9 (lH, d), 7.9-8.05 (lH, d)
  • Example 14: Preparation of 3-methylamino-4-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide:
    Figure imgb0059
     Light Yellow Crystal Yield: 49.3% IR(KBr, cm-1): 3350, 2960, 1640, 1420, 1310, 1165, 1030 NMR(CDCl3, ppm): 1.3-1.8 (6H, m), 2.2-2.55 (4H, m), 3.05 (3H, s), 3.35 (2H, s), 4.05-4.3 (2H, d), 4.7-4.95 (2H, d), 5.65-5.85 (2H, m), 6.6 (lH, s), 6.7-6.9 (lH, d), 7.4-7.65 (2H, b, Eliminated by the treatment with D20), 7.8-8.0 (lH, d)
  • Example 15: Preparation of 3-amino-4-[4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylaminol-1,2,5-thiadiazole:
  • (A) N-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenyl]-ethanediimidamide-tetrahydrochloride:
  • 3.76 g (0.01 mol) of 3-amino-4-[4-<4-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide obtained in example 7-(B) was dissolved in 89 ml of methanol, added with 7.13 ml of conc. hydrochloric acid while cooling at 5°C, and agitated at room temperature for 4 hours. The reaction mixture obtained was concentrated under reduced pressure after the completion of the reaction, and 8.9 ml of 2-propanol was added to the mixture followed by concentration under reduced pressure. This procedure was repeated three times, and water was removed by azetotropic distillation. The residue was added with 2.7 ml of absolute ethanol, ground thoroughly and cooled. Then the deposited crystal was quickly collected by filtration. The crystal obtained was used in the next reactian-after drying without purification because of its high hygroscopicity.
  • (B) 3-amino-4-(4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole:
  • 2.22 grams of N,N'-thiobisphthalimide (prepared by the method described in M.V. Kalnins, Canadian Journal of Chem., 44, 2111 (1966)) was added slowly to a mixture of 1.08 g of the crude crystal obtained in example 15-(A), 10 ml of CH2C12 and 0.69 g of triethylamine at room temperature under agitation, followed by agitation at room temperature for an additional 2 hours. The reaction mixture was added with 10 ml of 20% KOH aqueous solution and shaken thoroughly after the completion of the reaction; then the organic solvent layer was separated and dried with MgS04. The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel chromatograph column to purify the same, followed by elution with a mixed solution of ethyl acetate:ethanol:aqueous ammonia = 6:1:1. As a result, 0.29 g (Yield: 35.3%) was obtained as a light yellow oily product.
  • IR(neat, cm-1): 3390, 3250, 2950, 1620, 1565, 1420, 1300, 1170, 1040, 990, 830, 770 NMR(CDC13, ppm): 1.1-1.9 (6H, m), 2.1-2.7 (4H, m), 3.35 (2H, s), 3.8-4.3 (2H, m), 4.7-5.0 (2H, d), 5.3-5.6 (2H, b, Eliminated by the D20 treatment), 5.4-5.9 (2H, m), 6.55 (lH, s), 6.6-6.8 (lH, d), 7.75-8.0 (lH, d)
  • Example 16: Preparation of 3-amino-4-<4-(4-dimethylaminomethyl- pyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole:
  • In accordance with the procedure of example 15-(A) and 15-(B) but using 3.36 grams (0.01 mol) of 3-amino-4-<4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,5-thiadiazole-1-oxide- obtained in example ll-(B), there was obtained 0.28 g (Yield: 8.8%) of the captioned compound as a light yellow oily product.
  • IR(neat, cm-1): 3400, 3300, 1620, 1570, 1300, 1250, 1025, 825, 770, 620 NMR(CDC13, ppm): 2.25 (6H, s), 3.37 (2H, s), 3.75-4.2 (2H, d), 4.65-4.95 (2H, d), 5.15-5.6 (3H, b, Eliminated by the D20 treatment), 5.5-5.85 (2H, m), 6.65 (1H, s), 6.6-6.8 (lH, d), 7.8-8.0 (1H, d)
  • Example 17: Preparation of 2-amino-5-[4-<4-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1,3,4-thiadiazole:
  • (A) 2-bromo-5-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,3,4-thiadiazole:
  • 1.5 grams (5.7 m mol) of 4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine (obtained in example 1-(A)) was dissolved in 20 ml of ethanol, added with 1.4 g (5.7 m mol) of 2,5-dibromo-l,3,4-thiadiazole (prepared by the method described in R. Stolle and K. Fehrenbach, J. Prakt. Chem., 122, 289 (1929)) and 1 ml of triethylamine, and then refluxed for 10 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with ethyl acetate. As a result, 0.82 g (Yield: 36%) of the captioned compound was obtained in a colorless crystal form. The melting point of the crystal obtained by recrystallization from methanol was 121.5 to 1230C.
  • IR(KBr, cm-1): 3360, 2930, 1610, 1530, 1410, 1290, 1040 NMR(CDCl3, ppm): 1.4-1.8 (6H, m), 2.2-2.6 (4H, m), 3.35 (2H, s), 4.0-4.2 (2H, d), 4.8-5.0 (2H, d), 5.6-5.9 (2H, m), 6.6 (lH, s), 6.7-7.0 (lH, d), 7.2-7.4 (lH, b, Eliminated by the D20 treatment), 7.85-8.05 (lH, d)
  • (B) 2-amino-5-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2- butenylamino]-1,3,4-thiadiazole:
  • 0.7 grams (1.78 m mol) of the bromo product obtained in example 17-(A) was dissolved in 15 ml of 10% ammonia- methanol solution, and reacted in a sealed tube at 100oC for 2 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 9:1. Whereupon, 0.22 g (Yield: 34%) of the captioned compound was obtained as a colorless crystal having a melting point of 85 to 90°C.
  • IR(KBr, cm-1): 3200, 2940, 1610, 1560, 1420, 1285 NMR(CDC13): 1.3-1.6 (6H, m), 2.0-2.25 (4H, m), 3.2 (2H, s), 3.6-3.8 (2H, d), 4.5-4.7 (2H, d), 5.4-5.7 (2H, m), 6.5 (lH, s), 6.6-6.8 (lH, d), 7.0-7.7 (3H, b, Eliminated by the D20 treatment), 7.75-8.0 (lH, d)
  • Example 18: Preparation of 2-methylamino-5-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,3,4-thiadiazole:
    Figure imgb0060
    Yield: 21%
  • Melting Point: 53 to 55°C IR(KBr, cm-1): 3280, 2950, 1620, 1510, 1410, 1040 NMR(CDCl3, ppm): 1.3-1.7 (6H, m), 2.2-2.5 (4H, m), 3.35 (3H, s), 3.4 (2H, s), 3.75-4.05 (2H, m), 3.55-3.7 (lH, m, Eliminated by the treatment with D20), 5.5-5.8 (2H, m), 6.6 (lH, s), 6.7-6.9 (lH, d), 7.8-8.0 (lH, d).
  • Example 19: Preparation of 3-amino-1-methyl-5-(4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-1,2,4-triazole:
  • (A) N-cyano-S-methyl-N'-[4-<4-(3-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenyl]-isothiourea:
  • 2.0 grams (7.7 m mol) of 4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenyamine (obtained in example 1-(A)) and 1.22 g (8.36 m mol) of dimethylcyanodithioimidecarbonate (prepared by the- method described in Japanese Patent Publication No. 46-26482) were dissolved in 20 ml of methanol and agitated at room temperature for 16 hours. The solvent was distilled off under reduced pressure after completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with ethyl acetate. As a result, 0.95 g (Yield: 34.5%) of the captioned compound having a melting point of 107°C was obtained.
  • IR(KBr, cm-1): 3250, 2940, 2170, 1610, 1550, 1520 NMR(CDCl3, ppm): 1.4-1.7 (6H, m), 2.2-2.5 (4H, m), 3.32 (3H, s), 3.95-4.23 (2H, m), 4.75-4.9 (2H, m), 5.6-5.8 (2H, m), 6.6-7.0 (3H, m, 1H was eliminated by the D20 treatment), 7.9 (lH, d) MS: M+ = 359
  • (B) 3-amino-l-methyl-5-[4-<4-(J-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-lH-1,2,4-triazole:
  • 0.85 g (2.37 m mol) of the compound obtained in (A) above was dissolved in 30 ml of ethanol, and added with 0.9 ml of methylhydrazine followed by reflux for 16 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification. As a result, 0.6 g (Yield: 71%) of the captioned compound was obtained as a colorless yellow oily product.
  • IR(neat, cm-1): 3350, 3200, 2950, 2870, 2800, 1610, 1550, 1480, 1420 NMR(CDCl3, ppm): 1.4-1.8 (6H, m), 2.25-2.5 (4H, m), 3.32 (3H, s), 3.38 (2H, s), 3.6-4.2 (2H, m) 4.75-5.0 (2H, m), 5.3-6.2 (4H, m, 2H were eliminated by the D20 treatment), 6.6 (lH, s), 6.7-6.9 (1H, d), 7.9 (lH, d) MS: M+ = 357
  • Example 20: Preparation of 2-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-lH-pyrimidin-4-one:
  • 1.55 g (5.93 m mol) of 4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine (obtained in example 1-(A)) and 0.85 g (5.98 m mol) of 2-methylthio-lH-pyrimidin-4-one were melted at 150°C for 1.5 hours. The mixture obtained was dissolved in a small amount of methanol after the completion of the reaction and passed through a silica gel chromatograph column for purification, followed by elution with an ethyl acetate:methanol = 4:1. As a result, l.lg (Yield: 52%) of the captioned compound was obtained as a colorless oily product.
  • IR(neat, cm-1): 3250, 2940, 1670, 1610, 1310, 1040 NMR(CDCl3, ppm): 1.35-1.8 (6H, m), 2.2-2.5 (4H, m), 3.35 (2H, s), 4.0-4.2 (2H, d), 4.7-4.9 (2H, d), 5.5-5.75 (lH, d), 5.6-5.9 (2H, m), 6.6 (1H, s), 6.7-6.9 (lH, d), 7.4-7.6 (lH, d), 7.8-8.0 (lH, d)
  • Example 21: Preparation of 5-dimethylaminomethyl-2-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one:
    Figure imgb0061
  • Colorless Oily Product Yield: 17% IR(neat, cm-1): 3290, 2950, 1660, 1300, 1035 NMR(CDCl3, ppm): 1.4-1.7 (6H, m), 2.2-2.5 (4H, m), 2.3 (6H, s), 3.35 (2H + 2H, s), 3.9-4.1 (2H, d), 4.8-5.0 (2H, d), 5.6-5.85 (2H, m), 5.9-6.3 (2H, b, Eliminated by the treatment with D20), 6.5-6.9 (2H, m), 7.55 (lH, s), 7.85-8.0 (lH, d)
  • Example 22: Preparation of 2-[4-<4-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-5-(3-pyridylmethyl)-1H-pyrimidin-4-one:
  • 1.24 grams (4.75m mol) of 4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamine and 1.5 g (6.07 m mol) of 2- nitroamino-5-(3-pyridylmethyl)-lH-pyrimidin-4-one were refluxed in 30 ml of pyridine under agitation for 20 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel- chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. Whereupon, 1.0 g (Yield: 47%) of the captioned compound was obtained as a colorless oily product.
  • IR(neat, cm-1): 3250, 3050, 2950, 2860, 1660, 1610, 1560, 1480 NMR(DMSO-d6, ppm): 1.4-1.7 (6H, m), 2.15-2.40 (4H, m), 3.35 (2H, s), 3.52 (2H, s), 3.8-4.1 (2H, m), 4.7-4.95 (2H, m), 5.5-5.7 (2H, m), 6.0-8.4 (10H, m, 2H were eliminated by the D20 treatment)
  • MS: M+ = 446
  • Example 23: Preparation of 5-(3-dimethylaminomethylbenzyl)-2-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-lH-pyrimidin-4-one:
  • 3.3 grams (12.6 m mol) of 4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamine and 4.8 g (14.8 m mol) of 2-nitroamino-5-(3-dimethylaminomethylbenzyl)-lH-pyrimidin-4-one were refluxed in 90 ml of pyridine under agitation for 20 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol:ammonia = 6:1:1. As a result, 1.1 g (Yield: 17.4%) of the captioned compound was obtained as a light brown oily product.
  • IR(neat, cm-1): 3300, 2970,;2900, 2850, 1660, 1615, 1565 NMR(CDCl3, ppm): 1.35-1.75 (6H, m), 2.15 (6H, s), 2.15-2.5 (4H, m), 3.28 (4H, s), 3.55 (2H, s), 3.85-4.1 (2H, m), 4.7-4.9 (2H, m), 5.5-5.7 (2H, m), 6.5-8.5 (10H, m, 2H were eliminated by the D20 treatment)
  • Example 24: Preparation of 5-(3-dimethylaminomethylbenzyl)-2- <4-(4-dimethylaminomethylpyridyl-2-oxy)-cis-2-butenylamino>-1H-pyrimidin-4-one:
    Figure imgb0062
  • Yield: 43% IR(neat, cm-1): 3275, 2960, 2850, 2800, 1660, 1610, 1565 NMR(CDCl3, ppm): 2.15 (6H, s), 2.18 (6H, s), 3.29 (4H, s), 3.55 (2H, s), 3.9-4.1 (2H, m), 4.1-4.7 (2H, b, Eliminated by the treatment with D2O), 4.7-4.9 (2H, m), 5.6-5.8 (2H, m), 6.5-8.0 (8H, m) MS: M+ = 462 Example 25: Preparation of 3-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-6-(3-pyridylmethyl)-1,2,4-triazin-5-one:
    Figure imgb0063
  • Colorless Crystal
  • Yield: 20%
  • Melting Point: 134 to 135°C IR(KBr, cm-1): 3250, 2950, 1660, 1420, 1020 NMR(DMSO-d6, ppm): 1.1-1.8 (6H, m), 2.0-2.6 (4H, m), 3.34 (2H, s), 3.79 (2H, s), 3.7-4.2 (2H, m), 4.6-5.0 (2H, m), 5.4-5.7 (2H, m), 6.61 (lH, s), 6.79 (lH, d), 7.4-7.7 (lH, m), 8.2-8.5 (2H, m)
  • Example 26: Preparation of 4-amino-6-[4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-lH-pyrimidin-2-one:
  • 2.0 grams (7.66 m mol) of 4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine and 0.23 g (1.26 m mol) of 4-amino-6-chloro-lH-pyrimidin-2-one hydrochloride were refluxed in 3 ml of water under agitation for 30 minutes. The deposited crystal was filtrated after the completion of the reaction and recrystallized from a mixed solvent of methanol and dimethylsulfoxide. As a result, 0.32 g (Yield: 68.0%). of the captioned compound was obtained in a colorless crystal form. The melting point of the crystal obtained was 224.7°C, at which temperature it decomposed.
  • IR(KBr, cm-1): 3350, 3150, 3050, 2950, 1650, 1610, 1520, 1420 NMR(DMSO-d6, ppm): 1.3-1.6 (6H, m), 2.2-2.5 (4H, m), 3.6 (2H, s), 3.8-4.0 (2H, m), 4.7 (lH, s), 4.75-4.9 (2H, m), 5.45-5.7 (2H, m), 6.2-6.4 (3H, b, Eliminated by the D20 treatment), 6.6-8.0 (3H, m)
  • Example 27: Preparation of 6-amino-5-[4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-3-one:
  • 1.0 grams (3.83 m mol) of 4- 4-(l-piperidinomethyl)pyridyl-2-oxy -cis-2-butenylamine and 0.6 g (3.8 m mol) of 6-amino-5-methylmercapto-l,2,4-triazin-3-one were stirred in 40 ml of ethanol at room temperature for 24 hours. The deposited crystal was filtrated after the completion of the reaction and recrystallized from ethanol. As a result, 0.73 g (Yield: 51%) of the captioned compound was obtained as a colorless crystal having a melting point of 170 to 180°C.
  • IR(KBr, cm-1): 3250, 2950, 1640, 1560, 1460, 1030 NMR(DMSO-d6, ppm): 1.3-1.8 (6H, m), 2.1-2.5 (4H, m), 3.35 (2H, s), 4.0-4.3 (2H, m), 4.7-5.0 (2H, m), 5.37 (2H, b, Eliminated by the D20 treatment), 6.61 (lH, s), 6.78 (lH, d), 7.5-8.0 (lH, b, Eliminated by the D20 treatment), 7.92 (lH, d), 11.42 (1H, b, Eliminated by the D20 treatment) MS: M+ = 371 Example 28: Preparation of 6-methylamino-5-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-3-one:
  • In accordance with the procedure of example 27 but using 1.2 grams (4.59 m mol) of 4-<4-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamine and 0.726 g (4.59 m mol) of 6-methylamino-5-mercapto-l,2,4-triazin-3-one, there was obtained 0.75 g (Yield: 42%) of the captioned compound in a colorless crystal form. The melting point of the crystal was 150 to 160°C, at which temperature it decomposed.
  • IR(KBr, cm-1): 3350, 2950, 1640, 1600, 1400, 1040 NMR(DMSO-d6, ppm): 1.2-1.8 (6H, m), 2.2-2.5 (4H, m), 3.69 (3H, d), 3.8-4.3 (2H, m), 4.7-5.0 (2H, m), 5.4-6.6 (2H, m), 6.54 (1H, s), 6.71 (1H, d), 7.29 (1H, d) wherein 5.4-6.6 (1H, b), 7.2-7.6 (1H, b) and 11.43 (lH, b) were eliminated by the D20 treatment. MS : M+ = 385
  • Example 29: Preparation of 6-amino-2-methyl-5-[4-<4-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-3-one:
    Figure imgb0064
  • Colorless Oily Product Yield: 43% IR(neat, cm-1): 3350, 2950, 1650, 1350, 1030 NMR(CDC13, ppm): 1.2-1.8 (6H, m), 2.2-2.6 (4H, m), 3.38 (3H, s), 3.36 (2H, s), 4.0-4.3 (2H, m), 4.7-5.0 (2H, m), 5.3-5.5 (2H, m), 5.2-6.1 (2H, b, Eliminated by the treatment with D20), 6.56 (1H, s), 6.69 (1H, d), 7.93 (1H, d), 8.46 (1H, b, Eliminated by the treatment with D20) MS: M+ = 385
  • Example 30: Preparation of 6-amino-5-[4-<4-(1-piperidinomethyl) pyridyl-2-oxy>trans-2-butenylamino]-1,2,4-triazin-3-one:
    Figure imgb0065
    Colorless Crystal Yield: 46.8%
  • Melting Point: 200 to 205°C (d) IR(KBr, cm-1) 3250, 2950, 1640, 1460, 1300, 1020 NMR(DMSO-d6, ppm): 1.2-1.8 (6H, m), 2.1-2.4 (4H, m), 3.32 (2H, s), 3.8-4.2 (2H, m), 4.6-4.9 (2H, m), 5.7-6.0 (2H, m), 6.59 (lH, s), 6.79 (lH, d), 7.87 (lH, d); 5.48 (lH, b), 7.5-7.9 (lH, b) and 11.48' (lH, b) were eliminated by the D20 treatment. MS: M+ = 371 Example 31: Preparation of 6-amino-5-<4-(4-dimethylamino- methylpyridyl-2-oxy)-cis-2-butenylamino>-1,2,4-triazin-3-one:
  • In accordance with the procedure of example 25 but using 0.7 grams (3.16 m mol) of 4-(4-dimethylamino- methylpyridyl-2-oxy)-cis-2-butenylamine (example 3-(A)) and 0.45 g (3.16 m mol)- of 6-amino-5-mercapto-1,2,4-triazin-3-one, there was obtained 0.65 g (Yield: 62%) of the captioned compound as a colorless crystal having a melting point of 180 to 190°C (d).
  • IR(KBr, cm-1): 3200, 2800, 1650, 1470, 1295, 1025 NMR(DMSO-d6, ppm): 2.15 (6H, s), 2.28 (2H, s), 3.9-4.4 (2H, m), 4.6-5.0 (2H, m), 5.5-5.9 (2H, m), 6.54 (lH, s), 7.71 (lH, d), 7.88 (lH, d); 5.27 (2H, b), 7.5-7.9 (lH, b) and 11.42 (lH, b) were eliminated by the D20 treatment.
  • MS: M+ = 331
  • Example 32: Preparation of 1-amino-2-[4-<6-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobuten-3,4-dione:
  • (A) 4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine: 2.34 grams of 60% sodium hydride was dispersed in 50 ml of absolute tetrahydrafuran and slowly added with 5.1 g (0.0586 mol) of 4-amino-cis-2-buten-l-ol. The reaction solution was cooled after agitation at 50°C for 30 minutes, and then'slowly added with 12.5 g (0.049 mol) of 2-bromo-6-(l-piperidinomethyl)pyridine (prepared by applying the method described in Japanese Patent Laid-Open Publication No. 58-170779) in 13 ml of tetrahydrofuran and refluxed for 72 hours under agitation. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was added with 200 ml of water and extracted with 200 ml of dichloromethane four times. The solvent was distilled off after drying an organic layer with magnesium sulfate anhydrous, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result., 7.05 g (Yield: 55.1%) of the captioned compound was obtained as a light brown oily product.
  • NMR(CDCl3, ppm): 1.3-1.8 (6H, m), 2.2-2.65 (4H, m), 2.75 (2H, s), 3.2-3.5 (2H, m), 4.7-5.0 (2H, d), 5.5-5.8 (2H, t), 6.25-7.6 (3H, m)
  • (B) l-methoxy-2-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-l-cyclobuten-3,4-dione:
  • 1.704 grams (0.012 mol) of dimethyl squalate (prepared by the process reported by Sideny Cohen et al, in J. Amer. chem. Soc., Vol. 88, 1533 (1966)) was dissolved in 50 ml of absolute methanol and cooled at 5°C. Then a solution of 3.132 grams (0.012 mol) of 4- 6-(l-piperidinomethyl)pyridyl-2-oxy - cis-2-butenylamine which was prepared by the method described in example 32-(A) in 20 ml of absolute methanol was dropped into the dimethyl squalate solution obtained above at 5°C of solution temperature, with stirring, and was stirred at room temperature for an additional 6 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column to purify the same, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 4.24 g (Yield: 95.3%) of the captioned compound was obtained as a light yellow oily product.
  • IR (neat, cm-1): 3350, 2970, 2850, 1810, 1718, 1615, 1460, 1385, 1035, 930, 810 NMR(CDCl3, ppm): 1.2-1.9 (6H, m), 2.15-2.8 (4H, m), 3.5 (2H, s), 4.0-4.4 (2H, m), 4.7-5.1 (2H, m), 4.3 (3H, s), 5.5-5.9 (2H, m), 6.4-7.6 (3H, m)
  • (C) 1-amino-2-(4-<6-(1-piperidinomethyl)pyridyl-2-oxy >-cis-2-butenylamino]-1-cyclobuten-3,4-dione:
  • 3.71 grams (0.01 mol) of l-methoxy-2-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobuten-3,4-dione obtained in (B) above was dissolved in 50 ml of absolute methanol to obtain a solution through which dry ammonia gas was passed at 50C of reaction temperature for 20 minutes, and then the solution was stirred at room temperature for an additional 2 hours. The deposited crystal was suctionally firtlated after the completion of the reaction, and recrystallized from methanol. As a result, 2.4 g (Yield: 67.5%) of the captioned compound having a melting point of 205 to 210°C (d) was obtained as a colorless crystal.
  • IR(KBr, cm-1): 3330, 3150, 2950, 1810, 1650, 1305, 1260, 1150, 1020, 985,;860, 800, 595 NMR(DMSO-d6 + CDC13, ppm): 1.1-1.7 (6H, m), 2.05-2.6 (4H, m), 2.8-3.2 (lH, bro, Eliminated by the D20 treatment), 3.4 (2H, s), 3.5-4.0 (2H, bro, Eliminated by the D2O treatment), 4.1-4.4 (2H, m), 4.6-5.0 (2H, m), 5.4-5.9 (2H, m), 6.3-7.6 (3H, m)
  • Example 33: Preparation of 1-methylamino-2-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino)-1-cyclobuten-3,4-dione:
    Figure imgb0066
    Colorless Crystal Yield: 64.9% Melting Point: 203 to 206°C (d) IR(KBr, cm-1): 3330, 3150, 2950, 1810, 1650, 1450, 1305, 1260, 1150, 1022, 990, 860, 800, 730, 600 NMR(DMSO-d6/CDC13, ppm): 1.2-1.8 (6H, m), 2.2-2.6 (4H, m), 3.4 (3H, s), 4.0-4.5 (2H, m), 4.6-5.0 (2H, m), 5.4-5.8 (2H, m), 6.3-7.6 (3H, m), 7.1-7.4 (lH, bro, Eliminated by the treatment with D20)
  • Example 34: Preparation of 3-amino-4-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylaminol-1,2,5-thiadzazole-1-oxide:
  • (A) 3-ethoxy-4-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide:
  • 3.0 grams (0.0115 mol) of 4-<6-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamine was dissolved in 50 ml of absolute ethanol, added with 2.1 g (0.0119 mol) of 3,4-diethoxy-l,2,5-thiadiazole-l-oxide (prepared by applying the method described in Japanese Patent Laid-Open Publication No. 56-40675) and agitated at room temperature for 2 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate : methanol = 4:1. As a result, 4.5 g (Yield: 96.6%) of the captioned compound was obtained as a colorless oily product.
  • IR(neat, cm-1): 3300, 2950, 1620, 1455, 1380, 1340, 1250, 1120, 1030, 805, 720, 620, 570, 530 NMR(CDCl3, ppm): 1.2-1.6 (3H, t), 1.3-1.9 (6H, m), 2.2-2.7 (4H, m), 3.5 (2H, s), 4.0-4.5 (2H, m), 4.3-4.7 (2H, q), 4.8-5.2 (2H, m), 5.5-6.0 (2H, m), 6.3-7.7 (3H, m)
  • (B) 3-amino-4-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1-oxide:
  • 1.0 grams (0.00247 mol) of 3-ethoxy-4-<4- 6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino -1,2,5-thiadiazole-1-oxide obtained in example 34-(A) was dissolved in 40 ml of absolute ethanol, added with 2 ml of ethanol solution saturated with ammonia gas and agitated at room temperature for 30 minutes. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 0.53 g (Yield: 57.1%) of the captioned compound having a melting point of 60 to 630C was obtained as a colorless crystal.
  • IR(KBr, cm-1): 3350, 3300, 3200, 2960, 1675, 1580, 1460, 1435, 1315, 1265, 1160, 1040, 1000, 880, 800, 660 NMR(DMSO-d5/CDCl3, ppm): 1.2-1.9 (6H, m), 2.1-2.7 (4H, m), 3.5 (2H, s), 3.9-4.4 (2H, m), 4.6-5.1 (2H, m), 5.4-5.9 (2H, m), 6.3-7.4 (3H, m), 7.1-7.8 (2H, bro, Eliminated by the D20 treatment.)
  • Example 35: Preparation of 3-methylamino-4-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-l,2,5-thiadiazole-l-oxide:
    Figure imgb0067
    Light Yellow Crystal Yield: 42.6% IR (KBr, cm-1): 3320, 2950, 1610, 1450, 1305, 1260, 1305, 1260, 1160, 1040, 850, 800,.735, 620 NMR(DMSO-d6, ppm): 1.1-1.9 (6H, m), 2.2-2.7 (4H, m), 2.95 (3H, s), 3.55 (2H, s), 3.9-4.4 (2H, m), 4.6-5.1 (2H, m), 5.4-6.0 (2H, m), 6.3-7.6 (3H, m)
  • Example 36: Preparation of 3-amino-4-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide:
  • (A) 3-ethoxy-4- [4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide:
  • 1.305 grams (0.005 mol) of the amine obtained in example 32-(A) was dissolved in 50 ml of absolute ethanol, added with 1.03 g (0.05 mol) of 3,4-diethoxy-1,2,5-thiadiazole-1,1-dioxide (prepared by applying the method described in Japanese Pateht Laid-Open Publication No. 56-40675) and agitated at room temperature for 24 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 1.59 g (Yield: 75.5%) of the captioned compound was obtained as an oily product.
  • (B) 3-amino-4-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole-1,1-dioxide:
  • 0.90 grams (0.00214 mol) of the ethoxy compound prepared in example 36-(A) was dissolved in 45 ml of absolute ethanol, added with 2 ml of methanol solution saturated with ammonia at room temperature and agitated at room temperature for 2 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 0.50 g (Yield: 59.6%) of the captioned compound having a melting point of 68 to 72°C was obtained as a light yellow crystal.
  • IR(KBr, cm-1): 3300, 2900, 1670, 1630, 1595, 1440, 1295, 1140, 1020, 980, 850, 640 NMR(DMSO-d6 - DCC13, ppm); 1.2-1.8 (6H, m), 2.1-2.6 (4H, m), 3.4 (2H, s), 3.8-4.2 (2H, m), 4.6-4.9 (2H, m), 5.5-5.9 (2H, m), 6.3-7.7 (3H, m).
  • Example 37: Preparation of 3-methylamino-4-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-betenylaminol-1,2,5-thiadiazole-1,1-dioxide:
    Figure imgb0068
    Light Yellow Crystal Yield: 51.8% Melting Point: 50 to 54°C IR(KBr, cm-1): 3300, 2900, 1630, 1440, 1400, 1300, 1150, 900, 750, 630, 540 NMR(CDCl3, ppm): 1.2-1.7 (6H, m), 2.2-2.6 (4H, m), 2.9 (3H, s), 3.4 (2H, s), 3.9-4.2 (2H, m), 4.7-5.0 (2H, m), 5.5-5.9 (2H, m), 6.4-7.8 (3H, m)
  • Example 38: Preparation of 3-amino-4-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,5-thiadiazole:
  • (A) N-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenyl- amino]-ethanediimidamide tetrahydrochloride:
  • 1.0 grams (0.00266 mol) of 3-amino-4-<4- 6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino -1,2,5-thiadiazole-1-oxide obtained in example 36-(B) was dissolved in 25.5 ml of methanol, added with 2.16 ml of conc. hydrochloric acid while cooling at 5°C, and agitated at room temperature for 4 hours. The reaction mixture obtained was concentrated under reduced pressure after the completion of the reaction, and 5 ml of 2-propanol was added to the mixture followed by concentration under reduced pressure. This procedure was repeated three times., and water was removed by azetotropic distillation. The residue was added with 2 ml of absolute ethanol, ground thoroughly and cooled. Then the deposited crystal was guickly collected by filtration. The crystal obtained was used in the next reaction after drying without purification because of its high hygroscopicity.
  • (B) 3-amino-4-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,s-thiadiazole:
  • 0.817 grams (0.00252 mol) of N, N'-thiobisphthalimide (prepared by the method described in M.V. Kalnis et al, Canadian Journal of Chem., 44, 2111 (1966)) was added slowly to a mixture of 1.2 g (0.00252 mol) of the crude crystal obtained in example 38-(A), 9.8 ml of CH2Cl2 and 1.05 ml of triethylamine at room temperature under agitation, and then agitated at room temperature for an additional 4 hours. The reaction mixture was added with 10 ml of 20% KOH aqueous solution and shaken thoroughly after the completion of the reaction: then the organic solvent layer was separated and dried with MgS04. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 0.24 g (Yield: 26.4%) of the captioned compound was obtained as a light yellow oily product.
  • IR(neat, cm-1): 3350, 2950, 1650, 1570, 1450, 1380, 1305, 1250, 1160, 1120, 1040, 1000, 860, 810 NMR(CDCl3, ppm): 1.1-1.8 (6H, m), 2.2-2.7 (4H, m), 3.6 (2H, s), 3.9-4.3 (2H, m), 4.8-5.0 (2H, m), 5.5-5.7 (2H, m), 5.9-7.5 (3H, m)
  • Example 39: Preparation of 2-amino-5-(4-<6-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1,3,4-thiadiazole:
  • (A) 2-bromo-5-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-l,3,4-thiadiazole:
  • 2.0 g (0.00765 mol) of 4-<6- (1-piperidinomethyl)pyridyl- 2-oxy>-cis-2-butenylamine (example 32-(A)) was dissolved in 30 ml of ethanol, added with 1.9 g (0.00779 mol) of 2,5-dibromo-1,3,4-thiadiazole (prepared by the method described in R. Stolle et al, J. Parkt. Chem., 122, 289 (1929)) and 2 ml of triethylamine; and refluxed for 7 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with ethyl acetate. As a result, 1.35 g (Yield: 42%) of the captioned compound was obtained as a colorless oily product.
  • IR(neat, cm-1): 3260, 2950, 1580, 1550, 1455, 1020 NMR(CDCl3, ppm): 1.4-1.7 (6H, m), 2.3-2.6 (4H, m), 4.75-4.95 (2H, m), 5.55-5.8 (2H, m), 6.35-7.5 (3H, m)
  • (B) 2-amino-5-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,3,4-thiadiazole:
  • 0.7 grams (0.00165 mol) of the bromo compound obtained in example 39-(A) was dissolved in 20 ml of methanol solution saturated with ammonia and reacted in a sealed tube at 100°C for 15 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 0.15 g (Yield: 25%) of the captioned compound having a melting point of 115 to 118°C was obtained as a colorless crystal.
  • IR(KBR, cm-1): 3250, 3160, 2950, 1575, 1510, 1450 NMR(DMSO-d6, ppm): 1.25-1.9 (6H, m), 2.85-3.25 (4H, m), 3.6-3.85 (2H, m), 4.1 (2H, s), 4.7-4.9 (2H, d), 5.4-5.7 (2H, m), 6.5-7.7 (3H, m), 3.2 (2H, bro, Eliminated by the D20 treatment.) M+ = 360
  • Example 40: Preparation of 2-methylamino-5-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylaminoJ-1,3,4-thiadiazole:
    Figure imgb0069
     Yield: 45.3% ; Melting Point: 75 to 80°C IR(KBr, cm-1): 3250, 2960, 1615, 1455, 1310 NMR(DMSO-d6, ppm): 1.35-1.7 (6H, m), 2.3-2.65 (4H, m), 3.2 (3H, s), 3.5 (2H, s), 3.7-4.0 (2H, m), 4.7-4.9 (2H, d), 5.5-5.7 (2H, m), 6.45 (lH, bro, Eliminated by the treatment with D20.)
  • Example 41: Preparation of 3-amino-1-methyl-5-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino[-lH-1,2,4-triazole:
  • (A) N-cyano-S-methyl-N'-[4-<6-(l-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenyl]-isothiourea:
  • 1.3 grams (0.00498 mol) of 4-<6-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamine (example 32-(A)) and 0.73 g (0.005 mol) of dimethylcyanodithioimide carbonate (prepared by the method described in Japanese Patent Publication No. 46-26482) were dissolved in 20 ml of methanol and stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with ethyl acetate. As a result, 1.57 g (Yield: 88%) of the captioned compound was obtained as a light yellow oily product.
  • IR(KBr, cm-1): 3250, 2180, 1550, 1450, 1260, 990, 800 NMR(CDCl3, ppm): 1.1-1.9 (6H, m), 2.2-2.7 (4H, m), 2.41 (3H, s), 3.48 (2H,; s), 4.0-4.4 (2H, m), 4.6-5.0 (2H, m), 5.3-6.0 (lH, m), 6.49 (lH, d), 6.83 (lH, d), 7.2-7.7 (lH, m)
  • (B) 3-amino-1-methyl-5-[4-<6-(1-piperidinomethyl)pyridyl-2- oxy>-cis-2-butenylamino]-1H-1,2,4-triazole:
  • 1.57 grams (0.00437 mol) of the compound obtained in example 41-(A) was dissolved in 20 ml of ethanol, added with 1.14 ml of methylhydrazine and refluxed for 5 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate : methanol = 4:1. As a result, 0.77 g (Yield: 49%) of the captioned compound was obtained as a light yellow oily product.
  • IR(neat, cm-1): 3350, 1610, 1560, 1450, 1310, 1260, 1040, 990, 760 NMR(CDCl3, ppm): 1.2-1.9 (6H, m), 2.2-2.7 (4H, m), 3.35 (3H, s), 3.47 (2H, s), 3.6-4.3 (2H, m), 4.7-5.3 (2H, m), 5.6-5.9 (2H, m), 6.49-6.86 (2H, m), 7.2-7.6 (lH, m), 2.6-4.3 (2H, bro., Eliminated by the D20 treatment.), 4.1-4.6 (lH, bro, Eliminated by the D20 treatment.)
  • Example 42: Preparation of 2-[4-<6-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one:
  • 3.1 grams (0.0119 mol) of 4- 6-(1-piperidinomethyl) pyridyl-2-oxy -cis-2-butenylamine (example 32-(A)) and 1.41 g (0.0112 mol) of 2-methylthio-1H-pyrimidin-4-one were melted at 150°C for 1.5 hours The mixture obtained was dissolved in a small amount of methanol after the completion of the reaction and passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 2.24 g (Yield: 54%) of the captioned compound was obtained as an oily product.
  • IR (neat, cm-1): 3300, 1680, 1600, 1450, 1300, 1220, 1030 NMR (CDC13, ppm): 1.2-1.9 (6H, m), 2.2-2.8 (4H, m), 3.50 (2H, s), 3.8-4.4 (2H, m), 4.6-5.1 (2H, m), 5.2-6.1 (4H, m), 6.49-6.81 (2H, m), 7.2-7.7 (lH, m)
  • Example 43: Preparation of 5-dimethylaminomethyl-2-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-lH-pyrimidin-4-one:
  • 2.0-grams (0.00563 mol) of 2-[4-<6-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-lH-pyrimidine-4-one (example 42) was dissolved in 50 ml of ethanol, added with 1 g of 50% dimethylamine aqueous solution, 0.8 g of 37% formaldehyde and 0.1 ml of acetic acid and refluxed for 2 hours. The solvent was distilled off under reduced pressure after the completion of the reaction, and the residue was passed through a silica gel chromatograph column for purification, followed by elution with a mixed solution of ethyl acetate:methanol = 4:1. As a result, 1.03 g (Yield: 44%) of the captioned compound was obtained as a colorless oily product.
  • IR (neat, cm-1): 1660, 1610, 1450, 1300, 1260, 1030 NMR (CDC13, ppm): 1.2-1.9 (6H, m), 2.2-2.7 (4H, m), 2.29 (6H, s), 3.27 (2H, s), 3.49 (2H, s), 3.7-4.3 (2H, m), 4.7-5.0 (2H, m), 5.6-5.8 (2H, m), 6.3-7.7 (3H, m)
  • Example 44: Preparation of 2-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylaminol-5-(3-pyridylmethyl)-lH-pyrimidin-4-one:
    Figure imgb0070
    Colorless Crystal Yield: 14% Melting Point: 40 to 47°C IR (cm-1): 3250, 2950, 1660, 1600, 1450 NMR (CDC13, ppm): 1.35-1.7 (6H, m), 2.27-2.55 (4H, m), 3.35 (2H, s), 3.5 (2H, s), 3.9-4.2 (2H, m), 4.6-4.8 (2H, m), 5.45-5.65 (2H, m), 5.6-6.1 (2H, bro, Eliminated by the treatment with D20.) 6.3-8.35 (8H, m), M+ = 446 ;
  • Example 45: Preparation of 5-dimethylaminomethylbenzyl-2-[4- <6-(1-pipelidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-4-one:
    Figure imgb0071
    Colorless Oily Product Yield: 20.0% IR (neat, cm-1): 3250, 2950, 1660, 1605, 1460 NMR (CDC13, ppm): 1.4-1.75 (6H, m), 2.2 (6H, s), 2.3-2.65 (4H, m), 3.48 (2H, s), 3.6 (4H, s), 3.96-4.3 (2H, m), 4.78-5.0 (2H, m), 5.65-5.85 (2H, m), 5.8-6.25 (2H, bro, Eliminated by the treatment with D20.), 6.3-7.57 (8H, m) M+ = 503
  • Example 46: Preparation of 3-[4-<6-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-6-(3-pyridylmethyl)-1,2,4-triazin-5-one:
    Figure imgb0072
    Yield: 13% Melting Point: 154 to 156°C IR(KBr, cm-1): 3250, 3050, 1600, 1580, 1460, 1310, 1020, 800, 710 NMR(CDC13, ppm): 1.1-1.9 (6H, m), 2.2-2.8 (4H, m), 3.63 (2H, s), 3.84 (2H, s), 3.7-4.4 (2H, m), 4.6-5.1 (2H, m), 5.2-5.9 (2H, m), 6.3-8.6 (7H, m), 7.0-9.0 (2H, bro, Eliminated by the treatment with D20.)
  • Example 47: Preparation of 4-amino-6-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1H-pyrimidin-2-one:
    Figure imgb0073
    Yield: 60% Melting Point: 214°C IR (KBr, cm-1): 3350, 3260, 3070, 2950, 2870, 2800, 1680, 1650, 1610, 1600, 1580, 1540 NMR (DMSO-d6, ppm): 1.3-1.6 (6H, m), 2.2-2.5 (4H, m), 3.4 (2H, s), 3.6-3.9 (2H, m), 4.5-4.9 (3H, m), 5.4-5.65 (2H, m), 6.3-7.5 (3H, m)
  • Example 48: Preparation of 4-amino-1-methyl-6-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-lH- pyrinidin-2-one:
    Figure imgb0074
    Yield: 27% IR(neat, cm-1): 3350, 3220, 2960, 1630, 1560, 1480, 1450 NMR(CDC13, ppm): 1.35-1.7 (6H, m), 2.25-2.6 (4H, m), 3.3 (3H, s), 3.43 (2H, s) 3.8-4.0 (2H, m), 4.7-4.9 (3H, m), 5.6-5.75 (2H, m), 6.35-7.5 (3H, m), M+ = 384
  • Example 49: Preparation of 6-amino-5-[4-<6-(1-piperiaino- methyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-3-one:
    Figure imgb0075
    Yield: 78% Melting Point: 160 to 170°C (d) IR(KBr, cm-1): 3250, 2950, 1640, 1450, 1300, 1260, 990, 760 NMR(DMSO-d6, ppm): 1.2-1.8 (6H, m), 2.2-2.6 (4H, m), 3.42 (2H, s), 3.9-4.3 (2H, m), 4.6-4.9 (2H, m), 5.5-5.9 (2H, m), 6.3-7.9 (3H, m), 5.28 (2H, bro, Eliminated by the treatment with D20), 11.12 (lH, bro, Eliminated by the treatment with D20), 7.2-7.9 (1H, bro, Eliminated by the treatment with D20) M+ = 371
  • Example 50: Preparation of 6-methylamino-5-[4-<6-(l-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-3-one:
    Figure imgb0076
    Colorless Oily Product Yield: 28% IR(neat, cm-1): 3350, 2950, 1680, 1600, 1450, 1260, 1030, 780 NMR(CDCl3, ppm): 1.3-1.8 (6H, m), 2.0-2.8 (4H, m), 3.52 (2H, s), 3.42 (3H, s), 4.0-4.3 (2H, m), 4.7-5.0 (2H, m), 5.4-5.8 (2H, m), 6.1-8.0 (3H, m), 6.1-6.4 (1H, bro, Eliminated by the treatment with D20) M+ = 385
  • Example 51: Preparation of 6-amino-2-methyl-5-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazin-3-one:
    Figure imgb0077
    Colorless Oily Product Yield: 14.7% IR (neat, cm-1): 3250, 1600, 1530, 1450, 1260, 1150, 990, 770 NMR(CDCl3, ppm): 1.2-1.9 (6H, m), 2.2-2.7 (4H, m), 3.35 (3H, s), 3.43 (2H, s), 3.9-4.4 (2H, m), 4.6-5.0 (2H, m), 5.4-6.8 (2H, m), 6.2-7.5 (3H, m), 5.35 (2H, bro, Eliminated by the treatment with D20), 8.30 (lH, bro, Eliminated by the treatment with D20) M+ = 385
  • Example 52: Preparation of 6-amino-3-mercapto-5-[4-<6-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1,2,4-triazine:
    Figure imgb0078
    Yield: 7% Melting Point: 100 to 106°C IR(KBr, cm-1): 3250, 2950, 1650, 1600, 1580, 1450, 1360, 1310, 1160, 1040 NMR(CDC13, ppm): 1.1-2.1 (6H, m), 2.2-3.0 (4H, m), 3.55 (2H, s), 3.9-4.4 (2H, m), 4.5-5.1 (2H, m), 5.4-6.9 (2H, m), 6.3-7.7 (3H, m) M+ = 387
  • Example 53: Preparation of 1-[4-<4-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-2-(2-pyridylmethylamino)-l-cyclobuten-3,4-dione:
    Figure imgb0079
    Colorless Crystal Yield: 79.6% Melting Point: 191 to 195°C IR(KBr, cm-1): 3200, 2950, 1800, 1643, 1560, 1480, 1430, 1290, 1163, 1050, 843, 780, 700, 635 . NMR(DMSO-d6/CDC13, ppm): 1.3-1.9 (6H, m), 2.25-2.6 (4H, m), 3.5 (2H, s), 4.3-4.7 (2H, m), 4.8-5.2 (2H, m), 5.0 (2H, s), 5.8-6.1 (2H, m), 6.8-8.8 (8H, m, 1H was eliminated by the D20 treatment.) MS: M+ = 447
  • Example 54: Preparation of l-[4-<4-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-2-(4-pyridylmethylamino)-1-cyclobuten-3,4-dione:
    Figure imgb0080
    Colorless Crystal Yield: 80.0% Melting Point: 202 to 205°C IR(KBr, cm-1): 3170, 2950, 2805, 1800, 1640, 1570, 1480, 1430, 1350, 1230, 1150, 1035, 995, 870, 800, 775, 620 NMR(DMSO-d6/CDC13, ppm): 1.1-1.8 (6H, m), 2.1-2.5 (4H, m), 3.4 (2H, s), 4.1-4.7 (4H, m), 4.7-5.1 (2H, m), 4.6-6.0 (2H, m), 6.7-8.7 (8H, m) MS: M+ = 447
  • Example 55: Preparation of l-[4-<6-(l-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-2-(2-pyridylmethylamino)-1-cyclobuten-3,4-dione:
    Figure imgb0081
    Colorless Crystal Yield: 69.8% Melting Point: 163 to 166°C IR(KBr, cm-1): 2990, 2950, 1800, 1640, 1570, 1420, 1305, 1260, 1150, 1020, 980, 800, 730, 610 NMR(DMSO-d6, ppm): 1.2-1.8 (6H, m), 2.15-2.7 (4H, m), 3.4 (2H, s), 4.25-4.6 (2H, m), 4.75-5.1 (2H, m), 5.6-6.0 (2H, m), 6.5-8.7 (8H, m) MS: M+ = 447
  • Example 56: Preparation of 1-[4-<6-(1-piperidinomethyl) pyridyl-2-oxy>-cis-2-butenylamino]-2-(4-pyridylmethylamino)-l-cyclobuten-3,4-dione:
    Figure imgb0082
    Colorless Crystal Yield: 30.0% Melting Point: 111 to 113°C IR(KBr, cm-1): 2980, 2950, 1800, 1620, 1430, 1260, 1150, 1020, 985, 940, 800, 740, 620, 500 NMR(DMSO-d6, ppm); 1.15-1.85 (6H, m), 2.1-2.7 (4H, m), 3.45 (2H, s), 4.15-4.55 (2H, m), 4.73 (2H, s), 4.6-5.0 (2H, m), 5.5-5.95 (2H, m), 6.4-8.7 (8H, m) MS: M+ = 447

Claims (19)

1. A pyridyloxy derivative represented by the general formula I:
Figure imgb0083
wherein X is
Figure imgb0084
[wherein Rl and R2 are individually hydrogen atoms or lower alkyl groups having 1 to 6 carbon atoms, or Rl and R2 form, together with the bonded nitrogen atom, a four to eight-membered heterocyclic ring which may have a further substituting group or groups; A is a straight-chain or branched-chain alkylene group having 1 to 6 carbon atoms) and Z is either one of the following groups:
Figure imgb0085
Figure imgb0086
Figure imgb0087
or
Figure imgb0088
(wherein R3, R4, R5, R6, R7, R8, R9, R10, Rll, R13, R14, R15, R16, R17 and R18 are individually hydrogen atoms or alkyl groups having 1 to 6 carbon atoms, alkenyl, alkynyl, aralkyl or heterocyclic aryl alkyl groups; or a four to eight-membered heterocyclic group is formed respectively by R3 and R4, R5 and R6, R7 and R8, R10 and Rll, Rl3 and R14, R16 and Rl7, together with the corresponding nitrogen atoms bonded therewith; R12 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, dialkylaminoalkyl group
Figure imgb0089
dialkylaminoalkyl-benzyl group
Figure imgb0090
or pyridylalkyl group
Figure imgb0091
wherein R19, R20, R21 and R22 are alkyl groups having 1 to 6 carbon atoms; q, r and s indicate integers of 1 to 6); G is a nitrogen or-carbon atom; p indicates 0, 1 or 2; Q indicates an oxygen or sulfur atom; and medically acceptable salts, hydrates and solvates thereof.
2. A derivative and medically;acceptable salts, hydrates, and solvates thereof of claim 1 wherein Z is a group of
Figure imgb0092
3. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 2 wherein R3 and R4 are individually hydrogen atoms, alkyl groups having 1 to 6 carbon atoms, alkynyl or aralkyl groups.
4. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 1 wherein Z is a group of
Figure imgb0093
5. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 4 wherein R5 and R6 are individually hydrogen atoms or alkyl groups having 1 to 6 carbon atoms or aralkyl groups.
6. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 1 wherein Z is a group of
Figure imgb0094
7. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 6 wherein R7 and R8 are individually hydrogen atoms or alkyl groups having 1 to 6 carbon atoms or aralkyl groups.
8. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 1 wherein Z is a group of
Figure imgb0095
9. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 8 wherein R9 is an alkyl group having 1 to 6 carbon atoms; and R10 and Rll are hydrogen atoms,
10. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 1 wherein Z is a group of
Figure imgb0096
11. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 1 wherein Z is a group of
Figure imgb0097
12. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 11 wherein R13 and R14 are hydrogen atoms; and R15 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
13. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 1 wherein Z is a group of
Figure imgb0098
14. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 13 wherein R16, R17 and R18 are individually hydrogen atoms or alkyl groups having 1 to 6 carbon atoms.
15. A derivative and medically acceptable salts, hydrates, and solvates thereof of claim 1 wherein X combines with a pyridine ring at the 4th position thereof.
16. A derivative and medically by acceptable salts, hydrates, and solvates thereof of claim 1 wherein X combines with a pyridine ring at the 6th position thereof.
17. A derivative and medically acceptable salts, hydrates, and solvates thereof claim 1 wherein R1 and R2 are lower alkyl groups having 1 to 6 carbon atoms; or R1 and R2 form, together with the bonded nitrogen atom, a four to eight-membered heterocyclic ring; A is a straight-chain alkylene group having 1 to 6 carbon atoms.
18. A pharmaceutical composition for the treatment of digestive ulcers which comprises at least one pyridyloxy derivative according to any of claims 1 to 17.
19. A pyridyloxy derivative according to any of claims 1 to 17 for the treatment of digestive ulcers.
EP85112416A 1984-10-02 1985-10-01 Pyridyloxy derivatives Expired - Lifetime EP0177016B1 (en)

Applications Claiming Priority (4)

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JP206690/84 1984-10-02
JP20669084A JPS6185365A (en) 1984-10-02 1984-10-02 Aminoalkylpyridyloxy derivative
JP5020785A JPS61207375A (en) 1985-03-12 1985-03-12 Pyridyloxy derivative
JP50207/85 1985-03-12

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EP0177016A2 true EP0177016A2 (en) 1986-04-09
EP0177016A3 EP0177016A3 (en) 1986-12-03
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DE (2) DE177016T1 (en)
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EP0282077A2 (en) * 1987-03-13 1988-09-14 Fujirebio Kabushiki Kaisha Pyridyloxy derivatives
EP0319903A2 (en) * 1987-12-07 1989-06-14 Ikeda Mohando Co., Ltd. Pyrimidone compound and pharmaceutically acceptable salts thereof
EP0582304A2 (en) * 1992-08-07 1994-02-09 FUJIREBIO Inc. Methods of producing amino butene derivatives
US5872139A (en) * 1996-06-17 1999-02-16 American Home Products Corporation Heterocyclymethylamino derivatives of cyclobutene-3,4-diones

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EP0569587A1 (en) * 1991-01-30 1993-11-18 Central Glass Company, Limited Phthalimide compound and production thereof
US6436972B1 (en) 2000-04-10 2002-08-20 Dalhousie University Pyridones and their use as modulators of serine hydrolase enzymes
EP4196793A1 (en) 2020-08-11 2023-06-21 Université de Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

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EP0282077A2 (en) * 1987-03-13 1988-09-14 Fujirebio Kabushiki Kaisha Pyridyloxy derivatives
EP0282077A3 (en) * 1987-03-13 1989-11-29 Fujirebio Kabushiki Kaisha Pyridyloxy derivatives
US4977267A (en) * 1987-03-13 1990-12-11 Fujirebio Kabushiki Kaisha Intermediates for pyridyloxy compounds having utility as anti-peptic ulcer agents
EP0319903A2 (en) * 1987-12-07 1989-06-14 Ikeda Mohando Co., Ltd. Pyrimidone compound and pharmaceutically acceptable salts thereof
EP0319903A3 (en) * 1987-12-07 1990-07-25 Ikeda Mohando Co., Ltd. Pyrimidone compound and pharmaceutically acceptable salts thereof
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EP0582304A3 (en) * 1992-08-07 1994-06-15 Fujirebio Kk Methods of producing amino butene derivatives
US5616711A (en) * 1992-08-07 1997-04-01 Fujirebio Inc. Methods of producing aminobutene derivatives
US5872139A (en) * 1996-06-17 1999-02-16 American Home Products Corporation Heterocyclymethylamino derivatives of cyclobutene-3,4-diones

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AU4813685A (en) 1986-04-10
DE3587416T2 (en) 1993-09-30
CA1275097A (en) 1990-10-09
ES8701161A1 (en) 1986-11-16
EP0177016A3 (en) 1986-12-03
EP0177016B1 (en) 1993-06-23
DE177016T1 (en) 1986-11-06
AU583536B2 (en) 1989-05-04
ES547458A0 (en) 1986-11-16
US4710498A (en) 1987-12-01
DE3587416D1 (en) 1993-07-29

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